Second generation non-nucleoside reverse transcriptase inhibitors (NNRTIs) etravirine and rilpivirine are essential components in the highly active antiretroviral therapy for the treatment of patients infected with human immunodeficiency virus type 1 (HIV-1). They are highly potent drugs against wild-type viruses and have exhibited excellent antiviral activities against some NNRTIs-resistant HIV-1 variants. In order to understand the underlying mechanism behind their robust resistance profile in comparison with the first generation NNRTIs nevirapine and efavirenz, it is necessary to quantitatively analyze their binding pockets in the wild-type HIV-1 reverse transcriptase (RT) and various HIV-1 RT mutants at the molecular level. Therefore, a high-level ab initio quantum chemical analysis was performed to decipher the molecular determinants for recognition of etravirine and rilpivirine by the wild-type RT and some RT mutants (K103N, K103N/Y181C, and K103N/L100I) of clinically important virus strains. Pair wise intermolecular interaction analysis determined the contribution of individual intermolecular interactions to the binding affinities between the second generation NNRTIs (etravirine or rilpivirine) and several variants of RTs, including the wild-type RT, and clinically relevant K103N, K103N/Y181C, and K103N/L100I mutant RTs. This quantitative analysis led to the identification of drug-protein interactions that persist despite mutations as well as to the evaluation of stabilization energy losses upon mutations. The results of this study enhanced our understanding of the molecular level mechanisms by which the second generation NNRTI drugs maintain their strong binding to mutant RTs. It is hoped that findings of this work would have a direct impact on designing new NNRTIs that are even more resilient to mutations in future.
11.evaluation of the coexpressed gene network of dreb0002www.iiste.org call f...Alexander Decker
This document analyzes the co-expressed gene network of DREB2A in Arabidopsis thaliana. DREB2A is a transcription factor involved in responses to drought and salt stress. The study uses the ATTED-II database to identify genes that are co-expressed with DREB2A. Several of the top co-expressed genes play roles in stress response pathways, such as heat shock proteins Hsp70b and heat stress transcription factors. The co-expressed network reveals that DREB2A interacts with proteins important for protecting plants from pathogens and stress-induced protein denaturation. Analysis of the co-expressed genes' expression patterns under different conditions provides insight into how their coordinated expression helps maintain homeostasis in response to
Evaluation of the coexpressed gene network of dreb2 aAlexander Decker
This document analyzes the coexpressed gene network of DREB2A in Arabidopsis thaliana. DREB2A is involved in responses to drought and salt stress. The network was analyzed using the ATTED-II database. Several genes were found to be closely coexpressed with DREB2A, including heat shock protein 70B (Hsp70b) and a heat stress transcription factor. These interacting genes play important roles in protecting plants from pathogen attack and helping proteins maintain proper folding under heat and salt stress. The expression patterns of DREB2A and four directly connected genes in the network vary across developmental stages and stress conditions, indicating their involvement in maintaining equilibrium under different environmental perturbations.
Review anti-cancer agents in medicinal chemistry, 2013Dr P Deepak
This document summarizes different types of kinase inhibitors for treating cancer. It discusses Type I inhibitors which compete with ATP for binding in the kinase catalytic site. While some Type I inhibitors have been FDA approved, they have limitations like low selectivity. Type II inhibitors bind in both the catalytic site and a lipophilic pocket, conferring higher selectivity. Type III or allosteric inhibitors bind outside the catalytic domain, providing subtle regulation. The document focuses on advantages of Type II inhibitors and strategies to design drugs that selectively inhibit targets or overcome drug resistance.
Collaborative science to identify novel inhibitors for the pseudokinase TRIB2Morgan Focas
This document summarizes research into developing inhibitors for the pseudokinase TRIB2. It describes synthesizing additional quantities of the compound GW881A, which was identified as a potent hit from screening the Published Kinase Inhibitor Set in a differential scanning fluorimetry assay of TRIB2. The synthesis involved a three-step route to obtain the final product. Additional analogs were screened in the TRIB2 assay to gain insight into structure-activity relationships, with the goal of improving potency. GW881A remained the most potent inhibitor identified.
This document summarizes research on the discovery of a novel class of orally active inhibitors of N-myristoyltransferase (NMT) that are trypanocidal, meaning they can kill the parasite Trypanosoma brucei which causes Human African Trypanosomiasis (HAT). Researchers screened over 63,000 compounds and identified a hit compound (1) that inhibited T. brucei NMT with low micromolar potency and also had activity against the parasite. They then optimized the hit through structure-activity relationship studies, improving potency against the enzyme and parasite as well as developing good oral pharmacokinetics. This led to a lead compound, DDD85646 (
Screening of receptor like kinase mutants of Arabidopsis thaliana using prote...Thomas Welch
This study screened 17 T-DNA knockout lines of receptor-like kinases in Arabidopsis thaliana for their response to protein extracts of the downy mildew pathogen Hyaloperonospora arabidopsidis using an oxidative burst assay. The assay found that knockout lines of ERL1 and BKK1 had significantly lower oxidative burst responses compared to the wild type, suggesting these genes may be involved in pathogen-associated molecular pattern triggered immunity against H. arabidopsidis. The results provide further evidence for the role of BKK1 in immunity and uncover the potential role of ERL1 in perceiving an obligate biotrophic pathogen, in contrast to previous research focusing on its response to nec
This document presents a literature review and proposed study on the effectiveness of volatiles produced by jasmonic acid (JA) seed treatment in tomato plants. The review discusses JA structure and biosynthesis, its role in direct and indirect plant defense responses, and interplant signaling via volatile organic compounds. It aims to determine if JA can induce plants to produce volatiles capable of signaling to other plants. The proposed study will examine effects of JA-treated and adjacent untreated tomato plants on the behavior of green peach potato aphids and two-spotted ladybirds using a y-tube olfactory assay.
A novel marker, ARM58, confers antimony resistance to Leishmania spp.Carola Schäfer
This document describes the identification of a novel genetic marker, LbrARM58, that confers antimony resistance to Leishmania species. Using a functional cloning strategy with genomic DNA libraries from antimony-resistant and sensitive L. braziliensis clinical isolates, researchers repeatedly selected a region on chromosome 20. This region contains the gene LbrM20.0210, which when overexpressed increases resistance to antimony (SbIII) in L. braziliensis and L. infantum in vitro and enhances parasite survival inside macrophages under antimony pressure. LbrM20.0210 encodes a previously uncharacterized protein with four repeats of a domain of unknown function that is unique to the Leishmania genus.
11.evaluation of the coexpressed gene network of dreb0002www.iiste.org call f...Alexander Decker
This document analyzes the co-expressed gene network of DREB2A in Arabidopsis thaliana. DREB2A is a transcription factor involved in responses to drought and salt stress. The study uses the ATTED-II database to identify genes that are co-expressed with DREB2A. Several of the top co-expressed genes play roles in stress response pathways, such as heat shock proteins Hsp70b and heat stress transcription factors. The co-expressed network reveals that DREB2A interacts with proteins important for protecting plants from pathogens and stress-induced protein denaturation. Analysis of the co-expressed genes' expression patterns under different conditions provides insight into how their coordinated expression helps maintain homeostasis in response to
Evaluation of the coexpressed gene network of dreb2 aAlexander Decker
This document analyzes the coexpressed gene network of DREB2A in Arabidopsis thaliana. DREB2A is involved in responses to drought and salt stress. The network was analyzed using the ATTED-II database. Several genes were found to be closely coexpressed with DREB2A, including heat shock protein 70B (Hsp70b) and a heat stress transcription factor. These interacting genes play important roles in protecting plants from pathogen attack and helping proteins maintain proper folding under heat and salt stress. The expression patterns of DREB2A and four directly connected genes in the network vary across developmental stages and stress conditions, indicating their involvement in maintaining equilibrium under different environmental perturbations.
Review anti-cancer agents in medicinal chemistry, 2013Dr P Deepak
This document summarizes different types of kinase inhibitors for treating cancer. It discusses Type I inhibitors which compete with ATP for binding in the kinase catalytic site. While some Type I inhibitors have been FDA approved, they have limitations like low selectivity. Type II inhibitors bind in both the catalytic site and a lipophilic pocket, conferring higher selectivity. Type III or allosteric inhibitors bind outside the catalytic domain, providing subtle regulation. The document focuses on advantages of Type II inhibitors and strategies to design drugs that selectively inhibit targets or overcome drug resistance.
Collaborative science to identify novel inhibitors for the pseudokinase TRIB2Morgan Focas
This document summarizes research into developing inhibitors for the pseudokinase TRIB2. It describes synthesizing additional quantities of the compound GW881A, which was identified as a potent hit from screening the Published Kinase Inhibitor Set in a differential scanning fluorimetry assay of TRIB2. The synthesis involved a three-step route to obtain the final product. Additional analogs were screened in the TRIB2 assay to gain insight into structure-activity relationships, with the goal of improving potency. GW881A remained the most potent inhibitor identified.
This document summarizes research on the discovery of a novel class of orally active inhibitors of N-myristoyltransferase (NMT) that are trypanocidal, meaning they can kill the parasite Trypanosoma brucei which causes Human African Trypanosomiasis (HAT). Researchers screened over 63,000 compounds and identified a hit compound (1) that inhibited T. brucei NMT with low micromolar potency and also had activity against the parasite. They then optimized the hit through structure-activity relationship studies, improving potency against the enzyme and parasite as well as developing good oral pharmacokinetics. This led to a lead compound, DDD85646 (
Screening of receptor like kinase mutants of Arabidopsis thaliana using prote...Thomas Welch
This study screened 17 T-DNA knockout lines of receptor-like kinases in Arabidopsis thaliana for their response to protein extracts of the downy mildew pathogen Hyaloperonospora arabidopsidis using an oxidative burst assay. The assay found that knockout lines of ERL1 and BKK1 had significantly lower oxidative burst responses compared to the wild type, suggesting these genes may be involved in pathogen-associated molecular pattern triggered immunity against H. arabidopsidis. The results provide further evidence for the role of BKK1 in immunity and uncover the potential role of ERL1 in perceiving an obligate biotrophic pathogen, in contrast to previous research focusing on its response to nec
This document presents a literature review and proposed study on the effectiveness of volatiles produced by jasmonic acid (JA) seed treatment in tomato plants. The review discusses JA structure and biosynthesis, its role in direct and indirect plant defense responses, and interplant signaling via volatile organic compounds. It aims to determine if JA can induce plants to produce volatiles capable of signaling to other plants. The proposed study will examine effects of JA-treated and adjacent untreated tomato plants on the behavior of green peach potato aphids and two-spotted ladybirds using a y-tube olfactory assay.
A novel marker, ARM58, confers antimony resistance to Leishmania spp.Carola Schäfer
This document describes the identification of a novel genetic marker, LbrARM58, that confers antimony resistance to Leishmania species. Using a functional cloning strategy with genomic DNA libraries from antimony-resistant and sensitive L. braziliensis clinical isolates, researchers repeatedly selected a region on chromosome 20. This region contains the gene LbrM20.0210, which when overexpressed increases resistance to antimony (SbIII) in L. braziliensis and L. infantum in vitro and enhances parasite survival inside macrophages under antimony pressure. LbrM20.0210 encodes a previously uncharacterized protein with four repeats of a domain of unknown function that is unique to the Leishmania genus.
Better ways to predict effectors for functional characterization and resistan...Kelsey Wood
This document discusses better methods for predicting plant pathogen effectors and identifying resistance genes. It finds that the traditional RXLR motif for predicting effectors is limited, especially in downy mildews which exhibit variants like GXLR. A novel WY domain is found to be prevalent in effectors from Phytophthora and downy mildews, identifying more candidates than RXLR alone. Some Lettuce downy mildew WY effectors can suppress plant immunity and elicit cell death. Recognition of specific WY effectors is linked to resistance in plant varieties, allowing rapid mapping of resistance genes. The study concludes the WY domain should be used for effector prediction in these pathogens, as RXLR alone
This document discusses the interplay between Mycobacterium tuberculosis (Mtb) and the host immune environment, particularly in the context of HIV/TB co-infection. It presents several key findings:
1. Mtb can detect and respond to environmental cues within the macrophage such as oxidative stress, nutrient limitation, and changes in pH and chloride concentration. This allows Mtb to sense its intracellular location and immune status.
2. Reporter strains of Mtb show an accelerated transcriptional response to stresses like nitric oxide in vaccinated mice, indicating the immune response is developing faster.
3. Drugs like isoniazid have greater activity against intracellular Mtb in naive mice, suggesting the bacteria replicate more in this
Src jbbr-20-120 Dr. ihsan edan abdulkareem alsaimary PROFESSOR IN MEDICAL M...dr.Ihsan alsaimary
Dr. ihsan edan abdulkareem alsaimary
PROFESSOR IN MEDICAL MICROBIOLOGY AND MOLECULAR IMMUNOLOGY
ihsanalsaimary@gmail.com
mobile : 009647801410838
university of basrah - college of medicine - basrah -IRAQ
1) The study identified SIRT2, a histone deacetylase, as a modulator of response to targeted cancer therapies through a genetic screen of epigenetic regulators.
2) Knockdown of SIRT2 conferred resistance to EGFR inhibitors in colon and lung cancer cell lines and to BRAF and MEK inhibitors in melanoma and colon cancer cell lines.
3) Loss of SIRT2 led to increased levels of phosphorylated ERK, suggesting it modulates resistance by regulating MEK kinase activity in the RAS-RAF-MEK-ERK signaling pathway.
25. comparative study of genetic variations as determined from marker systemsVishwanath Koti
Tomato (Solanum lycopersicum L.) is most important Solanacous vegetable grown worldwide for
its edible fruits. Various marker techniques have been successfully applied, either individually or in
combination to study the genetic diversity of this crop. A Study to assess the usefulness of different
markers system for analyzing the genetic diversity and relation between different varieties and to find out
correlation between marker systems revealed that all tested tomato cultivars could be differentiated from
each other based on either morphological/protein/RAPD markers individually, and can be applied for
grouping of cultivars, pedigree analysis and genetic diversity analysis. However, markers system used in
this study showed variations in understanding the genetic relation between studied varieties.
This document summarizes a study investigating how herstatin, an autoinhibitor of the epidermal growth factor receptor 2 (ErbB2/HER2) tyrosine kinase, modulates epidermal growth factor (EGF) and transforming growth factor beta (TGF-β) signaling pathways. The study found that herstatin expression in NIH3T3 cells decreased EGF-induced EGFR tyrosine phosphorylation and delayed receptor down-regulation. Herstatin almost completely blocked Akt stimulation by EGF and TGF-β but did not affect mitogen-activated protein kinase (MAPK) activation. While MAPK was fully activated, herstatin prevented TGF-β-induced DNA synthesis and
Herstatin is an autoinhibitor of the epidermal growth factor receptor 2 (ErbB2/HER2) that blocks receptor interactions and signaling. This study investigated how herstatin expression affects early epidermal growth factor (EGF) and transforming growth factor beta (TGF-β) signaling pathways and the downstream effects on cell proliferation in mouse fibroblasts. The results showed that herstatin decreased EGF-induced EGFR phosphorylation and delayed receptor downregulation. It also blocked EGF and TGF-β stimulation of the Akt pathway but not the MAPK pathway. While MAPK was fully activated, herstatin prevented TGF-β-induced DNA synthesis and EGF-induced proliferation. These
This document summarizes research on a class of compounds called thiazolides and their potential as antiviral agents, specifically against hepatitis B virus (HBV). Key points:
1. Thiazolides show promise as novel antiviral agents that could help treat HBV infections by acting through a non-resistance inducing mechanism. Nitazoxanide is a broad-spectrum thiazolide currently used as an antiparasitic drug.
2. The study synthesized and tested a wide range of thiazolide analogs for anti-HBV activity. Compound 3 showed potent and selective inhibition of HBV replication with low toxicity.
3. Structure-activity relationship analysis found good correlation
This presentation covers all approved therapy for the treatment of AIDS with their mechanism. It also includes some examples of new coming technology for treatment.
Multiplex pcr detection of gstm1, gstt1, and gstp1 gene variantsReema Mohammed
This document describes a multiplex PCR assay that can simultaneously detect the copy number status of the GSTM1 and GSTT1 genes (zero, one, or two copies) and the allelic status of the GSTP1 Ile105Val genetic variant in a single reaction. The assay was tested on DNA samples from 200 Danes, 100 Somalis, and 100 Greenlanders. Being able to distinguish between individuals with different copy numbers of GSTM1 and GSTT1 allows for investigating whether these genes influence factors like cancer susceptibility or drug response in a dose-dependent manner.
The document discusses a study on MRSA 252, a methicillin-resistant Staphylococcus aureus strain. It aims to construct a prophage-free host strain of MRSA 252 that can propagate lytic bacteriophages. 31 mutant strains of MRSA 252 were created using mitomycin C to induce prophages. Prophage screening using PCR found that mutations 7 and 8 did not contain the φSa2 and φSa3 prophages. Most mutant strains were susceptible to lytic phages in spot tests, but were resistant to some phages and high dilutions of others. Mutations 7 and 8 were resistant to all tested phages. The attempt to mobilize prophages from M
This document summarizes research into inhibiting the virulence of gram-positive bacteria by inhibiting the enzyme sortase A. The researchers used protein docking software to predict small molecule inhibitors from a library of compounds synthesized via the Ugi 4-component reaction. Solubility modeling was used to select Ugi products likely to precipitate out of solution and be purified easily. Selected inhibitors were tested in a colorimetric assay to measure their ability to inhibit sortase A and decrease bacterial virulence. Future work will optimize reactions, docking, and assays to identify potent synthetic sortase A inhibitors.
Similarities of Antimalarial Resistance Genes in Plasmodium Falciparum Based ...TELKOMNIKA JOURNAL
The finding of P. falciparum chloroquine resistance (pfcrt) and P. falciparum multidrug resistance
1(pfmdr1) gene in P. falciparum has become an obstacle in treating malaria. The polymorphism between
the two genes may result in molecular functions, in cellular components, or in biological processes. The
objective of this research is to find similarities between the two genes in 3 components; cellular
components, molecular functions and biological processes, based on Gene Ontology. the similarity will be
counted semantically by path length approach with Wang method. The range of similarity values is 0-1.
After the similarity value examined; in Molecular Function the similarity is 1 due to the same drug
transmembrane transporter activity, in Cellular Component is 0,714, the similarity only at the same vacuole
food cells, and in Biological Processes is 1 due to the same proces in responding to drug. Therefore, this
research proves both genes have similarities based on gene ontology.
This study validated the peroxisome targeting of two pathogen defense proteins in Arabidopsis thaliana, disease resistance protein 1 (DRP1) and nudix hydrolase homologue 15 (NUDT15), which were predicted to have peroxisome targeting signals (PTS). Experiments showed that an alternative splice variant of DRP1 (DRP1.2) localized to peroxisomes due to a functional PTS1 domain, while another variant (DRP1.1) remained cytosolic. Similarly, a splice variant of NUDT15 (NUDT15.2) was targeted to peroxisomes by its PTS1, but another variant (NUDT15.1) was
Priming for enhanced defence during Plant-Pathogen IntractionRakesh Punia
This document discusses plant defense priming, which enables plants to respond more rapidly and robustly to pathogens. Priming involves accumulating signaling components without activating full resistance. It is accompanied by induced resistance pathways. Priming techniques include chemical treatments and bio-priming with microbes. The molecular mechanisms of priming involve elevated pattern recognition receptors, dormant mitogen-activated protein kinases, and chromatin modifications that provide a stress memory. Priming shows potential for sustainable agriculture by reducing pesticide use through potentiated defenses.
The document discusses research into identifying potential ganglioside-binding proteins in Borrelia burgdorferi that causes Lyme disease. Bioinformatics analysis identified VlsE1 as a top hit that is known to be involved in late-stage Lyme disease. VlsE1 was cloned and expressed, and expression studies showed that 0.1 mM IPTG produced the best yield of soluble VlsE1. While some VlsE1 remained insoluble, work is ongoing to optimize expression and purification conditions to study the potential function of VlsE1 in binding gangliosides.
Prime-ome: "A molecular approach towards defense priming"Dhanya AJ
Prime-ome is the entire set of messenger RNA (mRNA) molécules or transcripts, proteins and metabolites produced or modified by an organism or system during the different stages of priming in plants and prime-omics is the study of prime-ome.
This study screened selected bioflavonoids from medicinal plants as potential inhibitors of the main protease (Mpro) of COVID-19 using molecular docking. Rutin showed the highest binding affinity to Mpro, while resveratol showed the lowest. Nelfinavir and lopinavir, used as standards, also showed strong binding. Apigenin, luteolin, and naringin exhibited good inhibition potential. Further research is needed to validate these bioflavonoids as COVID-19 treatments and investigate their effects on other viral targets.
Genome–Wide Analysis and Expression Pattern of the AP2/ERF Gene Family in Kiw...Agriculture Journal IJOEAR
—APETALA2/ethylene response factor (AP2/ERF) transcription factors play important roles in the response to abiotic stresses. It is now possible to identify all of the AP2/ERF genes in the kiwifruit genome because the kiwifruit genome project has been completed. 183 AP2/ERF genes were identified and compared with AP2/ERF genes from Arabidopsis in this study. The 183 AP2/ERF kiwifruit genes were classified into four subfamilies: DREB (64), ERF (94), AP2 (19) and RAV (5), as well as one soloist. RNA-sequence and Quantitative RT-PCR (qRT-PCR) analysis results showed that 20 genes were responsive to waterlogging stress, suggesting that AP2/ERF transcription factors play important roles in the response to waterlogging stress in kiwifruit
This document describes the development of a label-free targeted LC-MS proteomic workflow to identify and validate biomarkers of kinase inhibition. The method was applied to characterize inhibitors of protein kinase CK2 (CK2). Eight commercially available CK2 inhibitors were evaluated in human cell lines. CX-4945 and inhibitor VIII were found to most effectively inhibit CK2. Elongation factor 1-delta and eukaryotic translation initiation factor 2B were identified as biomarkers of CK2 inhibition, with IF2B demonstrating superior ability to monitor cellular CK2 activity. The targeted proteomics approach provides a robust platform for studying kinase inhibitors without phosphopeptide enrichment and can be adapted to other kinase-inhibitor studies
This document discusses epigenetically mediated toxicity and provides three key points:
1. Epigenetic modulation represents an intricate intersection of pharmacology, toxicology, and genotoxicity. It involves complex and reversible modifications to DNA and histones that can be influenced by environmental and therapeutic factors.
2. Toxicities associated with epigenetic modulation include effects on reproductive, hematopoietic, and developmental systems. However, there is no unique pattern of human epigenetic toxicities. Transgenerational toxicity is a concern but has not been well-studied.
3. Certain human disorders like Rett syndrome are caused by aberrant epigenetic regulation. Environmental stress can also cause heritable ep
HIV reverse transcriptase is the primary target of AIDS drugs. It converts HIV's RNA code into DNA for viral replication. There are two classes of inhibitors: nucleoside analogs and non-nucleoside inhibitors (NNRTIs). NNRTIs bind to a site near the active site and prevent conformational changes needed for viral replication. Using composite binding sites from multiple structures allows rational drug design of new NNRTIs with higher inhibitory activity and lower toxicity than previous methods.
Better ways to predict effectors for functional characterization and resistan...Kelsey Wood
This document discusses better methods for predicting plant pathogen effectors and identifying resistance genes. It finds that the traditional RXLR motif for predicting effectors is limited, especially in downy mildews which exhibit variants like GXLR. A novel WY domain is found to be prevalent in effectors from Phytophthora and downy mildews, identifying more candidates than RXLR alone. Some Lettuce downy mildew WY effectors can suppress plant immunity and elicit cell death. Recognition of specific WY effectors is linked to resistance in plant varieties, allowing rapid mapping of resistance genes. The study concludes the WY domain should be used for effector prediction in these pathogens, as RXLR alone
This document discusses the interplay between Mycobacterium tuberculosis (Mtb) and the host immune environment, particularly in the context of HIV/TB co-infection. It presents several key findings:
1. Mtb can detect and respond to environmental cues within the macrophage such as oxidative stress, nutrient limitation, and changes in pH and chloride concentration. This allows Mtb to sense its intracellular location and immune status.
2. Reporter strains of Mtb show an accelerated transcriptional response to stresses like nitric oxide in vaccinated mice, indicating the immune response is developing faster.
3. Drugs like isoniazid have greater activity against intracellular Mtb in naive mice, suggesting the bacteria replicate more in this
Src jbbr-20-120 Dr. ihsan edan abdulkareem alsaimary PROFESSOR IN MEDICAL M...dr.Ihsan alsaimary
Dr. ihsan edan abdulkareem alsaimary
PROFESSOR IN MEDICAL MICROBIOLOGY AND MOLECULAR IMMUNOLOGY
ihsanalsaimary@gmail.com
mobile : 009647801410838
university of basrah - college of medicine - basrah -IRAQ
1) The study identified SIRT2, a histone deacetylase, as a modulator of response to targeted cancer therapies through a genetic screen of epigenetic regulators.
2) Knockdown of SIRT2 conferred resistance to EGFR inhibitors in colon and lung cancer cell lines and to BRAF and MEK inhibitors in melanoma and colon cancer cell lines.
3) Loss of SIRT2 led to increased levels of phosphorylated ERK, suggesting it modulates resistance by regulating MEK kinase activity in the RAS-RAF-MEK-ERK signaling pathway.
25. comparative study of genetic variations as determined from marker systemsVishwanath Koti
Tomato (Solanum lycopersicum L.) is most important Solanacous vegetable grown worldwide for
its edible fruits. Various marker techniques have been successfully applied, either individually or in
combination to study the genetic diversity of this crop. A Study to assess the usefulness of different
markers system for analyzing the genetic diversity and relation between different varieties and to find out
correlation between marker systems revealed that all tested tomato cultivars could be differentiated from
each other based on either morphological/protein/RAPD markers individually, and can be applied for
grouping of cultivars, pedigree analysis and genetic diversity analysis. However, markers system used in
this study showed variations in understanding the genetic relation between studied varieties.
This document summarizes a study investigating how herstatin, an autoinhibitor of the epidermal growth factor receptor 2 (ErbB2/HER2) tyrosine kinase, modulates epidermal growth factor (EGF) and transforming growth factor beta (TGF-β) signaling pathways. The study found that herstatin expression in NIH3T3 cells decreased EGF-induced EGFR tyrosine phosphorylation and delayed receptor down-regulation. Herstatin almost completely blocked Akt stimulation by EGF and TGF-β but did not affect mitogen-activated protein kinase (MAPK) activation. While MAPK was fully activated, herstatin prevented TGF-β-induced DNA synthesis and
Herstatin is an autoinhibitor of the epidermal growth factor receptor 2 (ErbB2/HER2) that blocks receptor interactions and signaling. This study investigated how herstatin expression affects early epidermal growth factor (EGF) and transforming growth factor beta (TGF-β) signaling pathways and the downstream effects on cell proliferation in mouse fibroblasts. The results showed that herstatin decreased EGF-induced EGFR phosphorylation and delayed receptor downregulation. It also blocked EGF and TGF-β stimulation of the Akt pathway but not the MAPK pathway. While MAPK was fully activated, herstatin prevented TGF-β-induced DNA synthesis and EGF-induced proliferation. These
This document summarizes research on a class of compounds called thiazolides and their potential as antiviral agents, specifically against hepatitis B virus (HBV). Key points:
1. Thiazolides show promise as novel antiviral agents that could help treat HBV infections by acting through a non-resistance inducing mechanism. Nitazoxanide is a broad-spectrum thiazolide currently used as an antiparasitic drug.
2. The study synthesized and tested a wide range of thiazolide analogs for anti-HBV activity. Compound 3 showed potent and selective inhibition of HBV replication with low toxicity.
3. Structure-activity relationship analysis found good correlation
This presentation covers all approved therapy for the treatment of AIDS with their mechanism. It also includes some examples of new coming technology for treatment.
Multiplex pcr detection of gstm1, gstt1, and gstp1 gene variantsReema Mohammed
This document describes a multiplex PCR assay that can simultaneously detect the copy number status of the GSTM1 and GSTT1 genes (zero, one, or two copies) and the allelic status of the GSTP1 Ile105Val genetic variant in a single reaction. The assay was tested on DNA samples from 200 Danes, 100 Somalis, and 100 Greenlanders. Being able to distinguish between individuals with different copy numbers of GSTM1 and GSTT1 allows for investigating whether these genes influence factors like cancer susceptibility or drug response in a dose-dependent manner.
The document discusses a study on MRSA 252, a methicillin-resistant Staphylococcus aureus strain. It aims to construct a prophage-free host strain of MRSA 252 that can propagate lytic bacteriophages. 31 mutant strains of MRSA 252 were created using mitomycin C to induce prophages. Prophage screening using PCR found that mutations 7 and 8 did not contain the φSa2 and φSa3 prophages. Most mutant strains were susceptible to lytic phages in spot tests, but were resistant to some phages and high dilutions of others. Mutations 7 and 8 were resistant to all tested phages. The attempt to mobilize prophages from M
This document summarizes research into inhibiting the virulence of gram-positive bacteria by inhibiting the enzyme sortase A. The researchers used protein docking software to predict small molecule inhibitors from a library of compounds synthesized via the Ugi 4-component reaction. Solubility modeling was used to select Ugi products likely to precipitate out of solution and be purified easily. Selected inhibitors were tested in a colorimetric assay to measure their ability to inhibit sortase A and decrease bacterial virulence. Future work will optimize reactions, docking, and assays to identify potent synthetic sortase A inhibitors.
Similarities of Antimalarial Resistance Genes in Plasmodium Falciparum Based ...TELKOMNIKA JOURNAL
The finding of P. falciparum chloroquine resistance (pfcrt) and P. falciparum multidrug resistance
1(pfmdr1) gene in P. falciparum has become an obstacle in treating malaria. The polymorphism between
the two genes may result in molecular functions, in cellular components, or in biological processes. The
objective of this research is to find similarities between the two genes in 3 components; cellular
components, molecular functions and biological processes, based on Gene Ontology. the similarity will be
counted semantically by path length approach with Wang method. The range of similarity values is 0-1.
After the similarity value examined; in Molecular Function the similarity is 1 due to the same drug
transmembrane transporter activity, in Cellular Component is 0,714, the similarity only at the same vacuole
food cells, and in Biological Processes is 1 due to the same proces in responding to drug. Therefore, this
research proves both genes have similarities based on gene ontology.
This study validated the peroxisome targeting of two pathogen defense proteins in Arabidopsis thaliana, disease resistance protein 1 (DRP1) and nudix hydrolase homologue 15 (NUDT15), which were predicted to have peroxisome targeting signals (PTS). Experiments showed that an alternative splice variant of DRP1 (DRP1.2) localized to peroxisomes due to a functional PTS1 domain, while another variant (DRP1.1) remained cytosolic. Similarly, a splice variant of NUDT15 (NUDT15.2) was targeted to peroxisomes by its PTS1, but another variant (NUDT15.1) was
Priming for enhanced defence during Plant-Pathogen IntractionRakesh Punia
This document discusses plant defense priming, which enables plants to respond more rapidly and robustly to pathogens. Priming involves accumulating signaling components without activating full resistance. It is accompanied by induced resistance pathways. Priming techniques include chemical treatments and bio-priming with microbes. The molecular mechanisms of priming involve elevated pattern recognition receptors, dormant mitogen-activated protein kinases, and chromatin modifications that provide a stress memory. Priming shows potential for sustainable agriculture by reducing pesticide use through potentiated defenses.
The document discusses research into identifying potential ganglioside-binding proteins in Borrelia burgdorferi that causes Lyme disease. Bioinformatics analysis identified VlsE1 as a top hit that is known to be involved in late-stage Lyme disease. VlsE1 was cloned and expressed, and expression studies showed that 0.1 mM IPTG produced the best yield of soluble VlsE1. While some VlsE1 remained insoluble, work is ongoing to optimize expression and purification conditions to study the potential function of VlsE1 in binding gangliosides.
Prime-ome: "A molecular approach towards defense priming"Dhanya AJ
Prime-ome is the entire set of messenger RNA (mRNA) molécules or transcripts, proteins and metabolites produced or modified by an organism or system during the different stages of priming in plants and prime-omics is the study of prime-ome.
This study screened selected bioflavonoids from medicinal plants as potential inhibitors of the main protease (Mpro) of COVID-19 using molecular docking. Rutin showed the highest binding affinity to Mpro, while resveratol showed the lowest. Nelfinavir and lopinavir, used as standards, also showed strong binding. Apigenin, luteolin, and naringin exhibited good inhibition potential. Further research is needed to validate these bioflavonoids as COVID-19 treatments and investigate their effects on other viral targets.
Genome–Wide Analysis and Expression Pattern of the AP2/ERF Gene Family in Kiw...Agriculture Journal IJOEAR
—APETALA2/ethylene response factor (AP2/ERF) transcription factors play important roles in the response to abiotic stresses. It is now possible to identify all of the AP2/ERF genes in the kiwifruit genome because the kiwifruit genome project has been completed. 183 AP2/ERF genes were identified and compared with AP2/ERF genes from Arabidopsis in this study. The 183 AP2/ERF kiwifruit genes were classified into four subfamilies: DREB (64), ERF (94), AP2 (19) and RAV (5), as well as one soloist. RNA-sequence and Quantitative RT-PCR (qRT-PCR) analysis results showed that 20 genes were responsive to waterlogging stress, suggesting that AP2/ERF transcription factors play important roles in the response to waterlogging stress in kiwifruit
This document describes the development of a label-free targeted LC-MS proteomic workflow to identify and validate biomarkers of kinase inhibition. The method was applied to characterize inhibitors of protein kinase CK2 (CK2). Eight commercially available CK2 inhibitors were evaluated in human cell lines. CX-4945 and inhibitor VIII were found to most effectively inhibit CK2. Elongation factor 1-delta and eukaryotic translation initiation factor 2B were identified as biomarkers of CK2 inhibition, with IF2B demonstrating superior ability to monitor cellular CK2 activity. The targeted proteomics approach provides a robust platform for studying kinase inhibitors without phosphopeptide enrichment and can be adapted to other kinase-inhibitor studies
This document discusses epigenetically mediated toxicity and provides three key points:
1. Epigenetic modulation represents an intricate intersection of pharmacology, toxicology, and genotoxicity. It involves complex and reversible modifications to DNA and histones that can be influenced by environmental and therapeutic factors.
2. Toxicities associated with epigenetic modulation include effects on reproductive, hematopoietic, and developmental systems. However, there is no unique pattern of human epigenetic toxicities. Transgenerational toxicity is a concern but has not been well-studied.
3. Certain human disorders like Rett syndrome are caused by aberrant epigenetic regulation. Environmental stress can also cause heritable ep
HIV reverse transcriptase is the primary target of AIDS drugs. It converts HIV's RNA code into DNA for viral replication. There are two classes of inhibitors: nucleoside analogs and non-nucleoside inhibitors (NNRTIs). NNRTIs bind to a site near the active site and prevent conformational changes needed for viral replication. Using composite binding sites from multiple structures allows rational drug design of new NNRTIs with higher inhibitory activity and lower toxicity than previous methods.
1. 22Rv1 prostate cancer cells were treated with enzalutamide to generate resistant cells (22Rv1-R).
2. Microscopy showed no morphological differences between 22Rv1 and 22Rv1-R cells. Western blot analysis revealed higher MDR1 expression in 22Rv1-R cells.
3. MTT assay demonstrated 22Rv1-R cell viability remained stable in increasing enzalutamide concentrations, indicating resistance, while 22Rv1 cell viability decreased.
This research article investigates how plant ribosome-inactivating proteins (RIPs) induce cellular stress responses in human cancer cells. The researchers found that two human cancer cell lines exposed to three RIPs - ricin, riproximin and volkensin - activated the unfolded protein response (UPR), a stress response pathway in the endoplasmic reticulum. This suggests the UPR induction better explains the cellular effects of RIPs, as apoptosis was induced even when some protein translation was still occurring due to ribosomal damage. The study provides new insights into the molecular mechanisms by which RIPs exert their toxic effects on cells.
This document provides an overview of antiretroviral therapies (ART) used to treat HIV and issues with patient adherence to these treatment regimens. It discusses the history of HIV/AIDS and the development of early treatments like AZT. The major classes of ART are described, including how they work to inhibit different stages of the HIV replication cycle. Challenges to effective adherence are reviewed, such as medication side effects, complex dosing schedules, and social/personal barriers patients may face. High adherence to combination ART is emphasized as critical for suppressing the virus and preventing drug resistance.
ABSTRACT- Multiple Drug resistance (MDR) tuberculosis timely diagnose is of utmost clinical relevance and needs to be diagnose at initial stages for the proper treatment. The current study was done to detect the several genes for MDR tuberculosis (TB) in clinical isolates by molecular tools. 60 clinical isolates were collected and subjected for AFB smear preparation, Nested PCR (IS6110) for mycobacterium tuberculosis complex detection and MDR TB PCR targeting rpoB, kat G, mab A promoter. 12 came positive for AFB smears, out of which 08 were pulmonary and 04 were extra pulmonary. Nested PCR targeting IS6110 gene was amplified at 123 base pairs with 340 base pairs as IC (internal control) was seen in 25 cases which include 19 pulmonary and 6 extra pulmonary. The Positive TB PCR specimens were subjected for MDRTB PCR Only 06 cases yielded, an amplicon of 315 bp confirming the rpoB gene resistance for resistance for rifampcin drug. In any of the 06 positives none of the other resistance gene other than rpoB was amplified. Targeting multiple genes at once, additional information will be gained from a single test run that otherwise would require several times the reagents and more time to perform. Current study signifies the usage of quick, cost effective, DNA sequences based method for MDR TB detection where disease will be diagnosed earlier and hence treatment would be started at an early stage.
Keywords: Multiple drug resistance, amplicon, Polymerase chain reaction, Nested PCR, Rifampicin.
Raghu Solanki presented on using nano diamonds for drug delivery of efavirenz to treat HIV. Key points:
- Nano diamonds are 2-8 nm in diameter and can attach drugs like efavirenz to their surface for delivery.
- Efavirenz is effective against HIV but has low bioavailability and drug resistance.
- Nano diamonds could help deliver efavirenz due to their biocompatibility and ability to increase drug solubility and provide sustained release.
- Experiments showed nano diamonds effectively adsorbed and released efavirenz in vitro and could deliver it across a blood brain barrier model while avoiding side effects.
Comparing Genetic Evolutionary Algorithms on Three Enzymes of HIV-1: Integras...CSCJournals
In this work, we utilized Quantitative Structure-Activity Relationship (QSAR) techniques to develop predictive models for inhibitors of the HIV-1 enzymes Integrase, HIV-Protease, and Reverse Transcriptase. Each predictive model was composed of quantitative drug characteristics that were selected by genetic evolutionary algorithms, such as Genetic Algorithm (GE), Differential Evolutionary Algorithm (DE), Binary Particle Swarm Optimization (BPSO), and Differential Evolution with Binary Particle Swarm Optimization (DE-BPSO). After characteristic selection, each model was tested with machine-learning algorithms such as Multiple Linear Regression (MLR), Support Vector Machine (SVM), and Multi-Layer Perceptron neural networks (MLP/ANN). We found that a combination of DE-BPSO combined with Multi-Layer Perceptron produced the most accurate predictive models as measured by R2, the statistical measure of proportion of variance in prediction values, and root-mean-square-error (RMSE) of prediction values compared to observed values. As for the models themselves: the best predictors for Integrase inhibitor included mass-weighted centred Broto-Moreau autocorrelation values, Moran autocorrelations, and eigenvalues of Burden matrices weighted by I-states; the best predictors for HIV-Protease inhibitors included the second Zagreb index value, the normalized spectral positive sum from Laplace matrix, and the connectivity-like index of order 0 from edge adjacency mat; and the best predictors for Reverse Transcriptase inhibitors included the number of hydrogen atoms, the molecular path count of order 7, the centred Broto-Moreau autocorrelation of lag 2 weighted by Sanderson electronegativity, the P_VSA-like on ionization potential, and the frequency of C – N bonds at topological distance 3.
The role of integrase inhibitors in first line and later antiretroviral thera...hivlifeinfo
This document discusses integrase inhibitors for the treatment of HIV. It summarizes clinical trials comparing the integrase inhibitors raltegravir, elvitegravir, and dolutegravir to efavirenz and atazanavir/ritonavir in treatment-naive patients. The studies found integrase inhibitors were as effective as or better than comparators in suppressing HIV, with fewer side effects. Raltegravir given once daily was inferior to twice daily dosing. Elvitegravir/cobicistat was found to be noninferior to efavirenz and atazanavir/ritonavir through 144 weeks.
The role of integrase inhibitors in first line and later antiretroviral thera...Hivlife Info
This document discusses integrase inhibitors for the treatment of HIV. It summarizes clinical trials comparing the integrase inhibitors raltegravir, elvitegravir, and dolutegravir to efavirenz and atazanavir/ritonavir in treatment-naive patients. The studies found integrase inhibitors were as effective as or better than comparators in suppressing HIV, with fewer side effects. Raltegravir given once daily was inferior to twice daily dosing. Elvitegravir/cobicistat was found to be noninferior to efavirenz and atazanavir/ritonavir through 144 weeks.
This research article describes how plant pathogens have evolved to counteract central nodes of plant immune receptor networks. The researchers screened 165 pathogen effectors and identified 5 that suppressed cell death triggered by NLR immune receptors called NRCs. Further analysis showed that a cyst nematode effector and an oomycete effector specifically inhibited the function of two NRC proteins, NRC2 and NRC3, but not NRC4. The nematode effector bound directly to NRC2 and NRC3, while the oomycete effector acted through a host membrane trafficking protein to suppress NRC responses. This suggests that different pathogens have independently evolved effectors that target central nodes of the plant NLR network to promote infection. Coevolution with such
Reverse transcriptase inhibitors are a class of antiretroviral drugs used to treat HIV and hepatitis B. They work by inhibiting the reverse transcriptase enzyme required for viral replication. There are three main types: nucleoside/nucleotide analog reverse-transcriptase inhibitors which terminate DNA chain synthesis; and non-nucleoside reverse-transcriptase inhibitors which bind to and disable the reverse transcriptase enzyme. Resistance can develop through mutations that reduce drug binding affinity or allow removal of incorporated chain terminators.
Antiretroviral Resistance in HIV-1 Patients at a Tertiary Medical Institute in Saudi Arabia: a Retrospective Study and Analysis.
Journal Club,
Virology Rotation , 1/5/2019
Our genetic screen identified protein tyrosine phosphatase non-receptor type 11 (PTPN11) as a synthetic lethal interaction with BRAF inhibitors in BRAF mutant colon cancer cells. Suppression of PTPN11 using two independent shRNAs conferred sensitivity of resistant colon cancer cells to the BRAF inhibitor vemurafenib. Mechanistically, inhibition of PTPN11 blocks signaling from receptor tyrosine kinases to the RAS-MEK-ERK pathway, preventing acquired resistance to targeted cancer drugs resulting from receptor tyrosine kinase activation. Activated PTPN11 can serve as a biomarker of this drug resistance mechanism.
A perspective on dietary phytochemicals and cancerMonirg
This document discusses the role of oxidative stress and dietary phytochemicals in cancer prevention. It describes how oxidative stress causes an imbalance between reactive oxygen/nitrogen species and antioxidant defenses, potentially leading to DNA damage and cancer. The transcription factor Nrf2 plays a key role in activating antioxidant and detoxification genes. Many dietary phytochemicals have been shown to activate the Nrf2 pathway and protect against cancer by reducing oxidative stress. In addition, some phytochemicals can modify gene expression epigenetically by altering DNA methylation and histone modifications, including reactivating the Nrf2 pathway. Understanding these mechanisms may help develop new strategies for cancer prevention using phytochemicals.
Prion-like domains are low-complexity sequences found in about 1% of human proteins that are similar to yeast prion domains and confer prion-like properties. Two algorithms, PAPA and PrionScan, were developed to predict prion-like domains based on different criteria, amino acid composition and sequence from yeast proteins respectively. TAF15 is an RNA-binding protein that contains a prion-like domain and has been implicated in cancers and amyotrophic lateral sclerosis through gene fusions and mutations that alter its functions in transcription, splicing, and stress response. HNRPDL is also predicted to have a prion-like domain based on the PAPA algorithm and shares similar features to
This study examined genetic variants of IL28B rs12979860 as predictors of interferon-based therapy outcomes in people with hepatitis C virus (HCV) in Pakistan. The study found that HCV subgenotype 3a was most prevalent and had higher response rates to therapy than subtype 1a. Carriage of the IL28B rs12979860 CC genotype was associated with higher sustained virological response rates to therapy. In contrast, the IL28B rs8099917 polymorphism was not associated with therapy outcomes. The study concludes that HCV genotype and IL28B rs12979860 can help predict the effectiveness of interferon-plus-ribavirin combination therapy for HCV in Pakistan.
This study tested the hypothesis that a base-pairing interaction between nucleotide A79 in the Hepatitis Delta Virus (HDV) ribozyme and nucleotide U(-1) in its substrate is necessary for catalytic activity. Mutant ribozymes and substrates with variations at these positions were created and their kinetic activity analyzed. While mutation of A79 significantly reduced activity, further experiments found the hypothesis was incorrect. Additional nucleotides like A78 may interact with the substrate and warrant further investigation.
Structure-Activity Relationship Study of Synthetic Variants Derived from the ...CrimsonpublishersCJMI
Antimicrobial peptides are omnipresent in nature and act as the first line of defence of the host against infectious agents. A synthetic antimicrobial peptide derived from the N-terminus of human lactoferrin hLF(1-11) (GRRRRSVQWCA), displays antibacterial as well as antifungal activity in vitro and in vivo. In order to elucidate the mechanism of antimicrobial action of hLF(1-11), we have synthesised several peptides analogues derived from hLF(1- 11) to test their activity against various fungal and bacterial strains. In this way, a general trend on the importance of the order and position of amino acid residues for biological activity against various organisms could be drawn.
Structure-Activity Relationship Study of Synthetic Variants Derived from the ...CrimsonpublishersCJMI
Structure-Activity Relationship Study of Synthetic Variants Derived from the Highly Potent Human Antimicrobial Peptide hLF(1-11) by Carlo PJM Brouwer in Cohesive Journal of microbiology & infectious disease
Similar to Quantum Chemical Study of Molecular Recognition between Etravirine/Rilpivirine and the HIV-1 Reverse Transcriptase (20)
A novel, simple and economic reverse phase high performance liquid chromatography
(RP-HPLC) method has been developed for the quantification of duloxetine HCl (DLX) in
bulk and tablet dosage form with greater precision and accuracy. Separation was
achieved on inertsil ODS C18 (250mm×4.6×5micron) column in isocratic mode with
mobile phase consisting of Acetonitrile: Potassium dihydrogen phosphate buffer (pH
4.9) (43:57v/v) and conditions optimized were: flow rate was 1 ml/min. The detection
was carried out at 230 nm. The retention time of Duloxetine HCl was found to be 4.440
min. The method was validated as per ICH guidelines. Linearity was established for
Duloxetine HCl in the range10–120μg/ml with R2 value 0.999. The percentage recovery
of Duloxetine HCl was found to be in the range 99.82-100.25 %. The high recovery and
low relative standard deviation confirm the suitability of the proposed method for the
estimation of the drug in bulk and tablet dosage forms. Validation studies demonstrated that the proposed RP-HPLC method is simple, specific, rapid, reliable and reproducible for the determination of Duloxetine HCl in comparison to previous reported methods for Quality Control level.
Open access plays a pivotal role in propagating scientific information globally. It is completely user friendly and is open for all to access easily. Its salient features are, that it covers 50 worlds’s leading languages and have the facility of audio versions too. It invites every individual to share as well as explore scientific knowledge and research in the field of pharmaceutical sciences. It enhances scientific skills of the authors, readers, reviewers, editors and advisors by providing scientific credits. On whole it encourages each and everyone and attracts all towards the majestic world of science.
This document describes research into developing lyophilized biopolymer-clay hydrogels for drug delivery. Sulfathiazole (STH), a model drug, was intercalated into various clays including Laponite RDS and montmorillonite. The drug-clay mixtures were then incorporated into natural hydrogels of carrageenan or hydroxyethyl cellulose. The hydrogels were lyophilized to form xerogels. Differential scanning calorimetry and scanning electron microscopy showed the amorphous form of STH was intercalated in Laponite RDS within the structure of carrageenan. Optimal xerogels contained 1.5% carrageen
This article discusses psychological impacts and treatment of HIV/AIDS among Nigerian women, with a focus on cultural implications and promoting gender equality. It finds that Nigerian women are particularly vulnerable to HIV infection due to cultural and gender norms. Factors such as traditional gender roles, lack of education and economic opportunities, sexual violence, and harmful widowhood practices increase women's risk. The prevalence of HIV is higher among Nigerian women than men. Younger women are especially at risk. The article calls for addressing stigma, discrimination, and gender inequality to improve treatment and promote a more equitable response to the HIV epidemic in Nigeria.
Madridge Journal of AIDS (ISSN: 2638-1958); As a result of the increased availability of antiretroviral treatment, children infected with HIV can expect to live to adulthood and even to have long, productive lives.
Madridge Journal of AIDS (ISSN: 2638-1958); HIV-related stigma is a global issue. Its perpetuation varies in magnitude across and within countries, and serves as a major barrier to HIV prevention efforts.
Madridge Journal of AIDS (ISSN: 2638-1958); This pilot study investigated the efficacy of cognitive group interventions in reducing traumatic stress and human immunodeficiency virus (HIV) transmission behaviors in HIV seropositive women survivors of childhood sexual abuse.
Madridge Journal of AIDS (ISSN: 2638-1958); The placenta is an important blood-placental barrier organ that plays an important part during the time of pregnancy by allowing the selective exchange of molecules and gases.
This document discusses the lack of recognition of trans and gender diverse (TGD) people in discussions around HIV/AIDS in Australia. While TGD people have a high risk of contracting HIV, accounting for up to 4% of notifications in Australia, they are largely invisible in mainstream discourse and data collection on HIV. The document argues that more research is needed on the lived experiences of TGD people living with HIV in Australia to understand the social challenges they face and improve recognition, care, and support for this at-risk population.
Madridge Journal of AIDS (ISSN: 2638-1958); This article reviewed literature and scholarly studies related to psychosocial traumatic events among women in Nigeria. It conceptualized and discussed trauma from universal and cultural perspectives and different types of trauma.
Madridge Journal of AIDS (ISSN: 2638-1958); An approach to preventing new HIV infections is the expectation that people living with the virus will disclose their status to their partners, healthcare providers, and family members.
Madridge Journal of AIDS (ISSN: 2638-1958); This commentary will address how prosecutors can use existing legislation, innovative court-related programs, and smart prosecution techniques to fulfill their duty to protect public safety as it relates to persons with HIV in the criminal justice system.
Madridge Journal of AIDS (ISSN: 2638-1958); Haiti is one of the most severely resource-constrained countries in the Americas, experiencing high rates of HIV. Access to HIV care is the paramount barrier with a paucity of specialized care providers throughout the very rural country.
When I was asked to give a companion lecture in support of ‘The Philosophy of Science’ (https://shorturl.at/4pUXz) I decided not to walk through the detail of the many methodologies in order of use. Instead, I chose to employ a long standing, and ongoing, scientific development as an exemplar. And so, I chose the ever evolving story of Thermodynamics as a scientific investigation at its best.
Conducted over a period of >200 years, Thermodynamics R&D, and application, benefitted from the highest levels of professionalism, collaboration, and technical thoroughness. New layers of application, methodology, and practice were made possible by the progressive advance of technology. In turn, this has seen measurement and modelling accuracy continually improved at a micro and macro level.
Perhaps most importantly, Thermodynamics rapidly became a primary tool in the advance of applied science/engineering/technology, spanning micro-tech, to aerospace and cosmology. I can think of no better a story to illustrate the breadth of scientific methodologies and applications at their best.
(June 12, 2024) Webinar: Development of PET theranostics targeting the molecu...Scintica Instrumentation
Targeting Hsp90 and its pathogen Orthologs with Tethered Inhibitors as a Diagnostic and Therapeutic Strategy for cancer and infectious diseases with Dr. Timothy Haystead.
Immersive Learning That Works: Research Grounding and Paths ForwardLeonel Morgado
We will metaverse into the essence of immersive learning, into its three dimensions and conceptual models. This approach encompasses elements from teaching methodologies to social involvement, through organizational concerns and technologies. Challenging the perception of learning as knowledge transfer, we introduce a 'Uses, Practices & Strategies' model operationalized by the 'Immersive Learning Brain' and ‘Immersion Cube’ frameworks. This approach offers a comprehensive guide through the intricacies of immersive educational experiences and spotlighting research frontiers, along the immersion dimensions of system, narrative, and agency. Our discourse extends to stakeholders beyond the academic sphere, addressing the interests of technologists, instructional designers, and policymakers. We span various contexts, from formal education to organizational transformation to the new horizon of an AI-pervasive society. This keynote aims to unite the iLRN community in a collaborative journey towards a future where immersive learning research and practice coalesce, paving the way for innovative educational research and practice landscapes.
The technology uses reclaimed CO₂ as the dyeing medium in a closed loop process. When pressurized, CO₂ becomes supercritical (SC-CO₂). In this state CO₂ has a very high solvent power, allowing the dye to dissolve easily.
Sexuality - Issues, Attitude and Behaviour - Applied Social Psychology - Psyc...PsychoTech Services
A proprietary approach developed by bringing together the best of learning theories from Psychology, design principles from the world of visualization, and pedagogical methods from over a decade of training experience, that enables you to: Learn better, faster!
Current Ms word generated power point presentation covers major details about the micronuclei test. It's significance and assays to conduct it. It is used to detect the micronuclei formation inside the cells of nearly every multicellular organism. It's formation takes place during chromosomal sepration at metaphase.
ESR spectroscopy in liquid food and beverages.pptxPRIYANKA PATEL
With increasing population, people need to rely on packaged food stuffs. Packaging of food materials requires the preservation of food. There are various methods for the treatment of food to preserve them and irradiation treatment of food is one of them. It is the most common and the most harmless method for the food preservation as it does not alter the necessary micronutrients of food materials. Although irradiated food doesn’t cause any harm to the human health but still the quality assessment of food is required to provide consumers with necessary information about the food. ESR spectroscopy is the most sophisticated way to investigate the quality of the food and the free radicals induced during the processing of the food. ESR spin trapping technique is useful for the detection of highly unstable radicals in the food. The antioxidant capability of liquid food and beverages in mainly performed by spin trapping technique.
Describing and Interpreting an Immersive Learning Case with the Immersion Cub...Leonel Morgado
Current descriptions of immersive learning cases are often difficult or impossible to compare. This is due to a myriad of different options on what details to include, which aspects are relevant, and on the descriptive approaches employed. Also, these aspects often combine very specific details with more general guidelines or indicate intents and rationales without clarifying their implementation. In this paper we provide a method to describe immersive learning cases that is structured to enable comparisons, yet flexible enough to allow researchers and practitioners to decide which aspects to include. This method leverages a taxonomy that classifies educational aspects at three levels (uses, practices, and strategies) and then utilizes two frameworks, the Immersive Learning Brain and the Immersion Cube, to enable a structured description and interpretation of immersive learning cases. The method is then demonstrated on a published immersive learning case on training for wind turbine maintenance using virtual reality. Applying the method results in a structured artifact, the Immersive Learning Case Sheet, that tags the case with its proximal uses, practices, and strategies, and refines the free text case description to ensure that matching details are included. This contribution is thus a case description method in support of future comparative research of immersive learning cases. We then discuss how the resulting description and interpretation can be leveraged to change immersion learning cases, by enriching them (considering low-effort changes or additions) or innovating (exploring more challenging avenues of transformation). The method holds significant promise to support better-grounded research in immersive learning.
The cost of acquiring information by natural selectionCarl Bergstrom
This is a short talk that I gave at the Banff International Research Station workshop on Modeling and Theory in Population Biology. The idea is to try to understand how the burden of natural selection relates to the amount of information that selection puts into the genome.
It's based on the first part of this research paper:
The cost of information acquisition by natural selection
Ryan Seamus McGee, Olivia Kosterlitz, Artem Kaznatcheev, Benjamin Kerr, Carl T. Bergstrom
bioRxiv 2022.07.02.498577; doi: https://doi.org/10.1101/2022.07.02.498577
PPT on Direct Seeded Rice presented at the three-day 'Training and Validation Workshop on Modules of Climate Smart Agriculture (CSA) Technologies in South Asia' workshop on April 22, 2024.
ESA/ACT Science Coffee: Diego Blas - Gravitational wave detection with orbita...Advanced-Concepts-Team
Presentation in the Science Coffee of the Advanced Concepts Team of the European Space Agency on the 07.06.2024.
Speaker: Diego Blas (IFAE/ICREA)
Title: Gravitational wave detection with orbital motion of Moon and artificial
Abstract:
In this talk I will describe some recent ideas to find gravitational waves from supermassive black holes or of primordial origin by studying their secular effect on the orbital motion of the Moon or satellites that are laser ranged.
2. Madridge Journal of Novel Drug Research
26Madridge J Nov Drug Res.
ISSN: 2641-5232
Volume 1 • Issue 1 • 1000105
into the nascent viral DNA and block the addition of new
nucleotides, leading to the termination of DNA polymerization
[3,4]. A major problem pertaining to the use of NRTIs is that
they can also interfere with the DNA synthesis of the host cell,
causing serious side effects [5,6]. NNRTIs, on the other hand,
are highly specific non-competitive inhibitors of the HIV-1 RT
that stop the retroviral enzyme replication and do not inhibit
the host DNA polymerases [7,8,9]. By virtue of their selectivity,
potency and low toxicity to the host, they are fundamental
components in the highly active antiretroviral therapy
(HAART) for the treatment of HIV-1 infection [10].
Despite the structural diversity of NNRTIs, they all bind to
a common hydrophobic binding site in the RT enzyme
referred to as the non-nucleoside inhibitor binding pocket
(NNIBP), which is located at a distance of about 10 Å from the
enzyme’s polymerase active site [11,12]. Upon the binding of
NNRTIs to their allosteric binding sites, an induced
conformational change occurs at the enzyme’s polymerase
active site, rendering the enzyme catalytically inactive, thereby
stopping DNA replication [7]. First generation NNRTIs,
Nevirapine [13], Delavirdine [14], and Efavirenz [15] are drugs
with a low genetic barrier that requires a single point mutation
to trigger a high level resistance that severely impairs their
binding affinities to RT [16,17]. In contrast, second generation
NNRTIs Etravirine [18] and Rilpivirine [19] are potent inhibitors
with a higher genetic barrier to resistance which allows them
to retain potency against HIV-1 mutant strains that show
resistance to first generation NNRTIs [17,20].
Like the vast majority of drugs, NNRTIs bind to HIV-1 RT
via non covalent interactions (e.g. hydrogen bonding, π-π
stacking interactions, CH-π interactions and cation-π
interactions). The binding pose of an inhibitor into its receptor,
is determined by the collection of all the attractive and
repulsive forces between the inhibitor and its surrounding
interaction partners. Therefore, to gain an in-depth insight of
the molecular recognition between a NNRTI and its receptor,
it is of great importance to quantify the specific contributions
of each amino acid in the binding pocket to the binding
affinity between the NNRTI and its receptor. Deciphering the
energetic contribution of the individual residues in the ligand
binding pocket toward protein-NNRTI binding would have a
great influence on designing new inhibitors. Binding affinity
data determined experimentally represents the collective
contributions of all protein residues that form the ligand
binding pocket. Quantum chemical calculations, on the other
hand, offer a way to rigorously quantify the magnitude and
characterize the nature of individual intermolecular
interactions between ligands and their surrounding protein
residues.
Theaimofthepresentstudyistodeterminetheunderlying
reason behind the origin of high binding affinities of second
generation NNRTIs etravirine and rilpivirine to the wild-type
HIV-1 RT and some clinically relevant mutant variants of the
virus at the molecular level. For this purpose, data mining and
high level quantum chemical calculations were performed to
investigate the molecular recognition between etravirine/
rilpivirine and wild-type RT and mutated RTs. The energetic
contributions of the individual intermolecular interaction
between etravirine or rilpivirine and their surrounding amino
acids to the binding affinities between these inhibitors and
the various RTs were systematically analyzed in a pair wise
manner. The results of this study will not only shed light on
the molecular determinants for the molecular recognition of
NNRTIs in HIV-1 RT, but also enhance our understanding of
molecular recognition of drugs in protein in general.
Therefore, this work is expected to have a direct impact on
designing the next generation of NNRTIs with a higher
potency and even more resilience to mutations
Methods and Theory
Data Mining
The availability of crystal structures of etravirine and
rilpivirine bound to the wild-type HIV-1 RT and some clinically
important single and double point mutants from Protein Data
Bank (PDB) forms the basis of our quantum chemical analysis
present here. Table 1 lists the six PDB files of NNRTIs (etravirine
and rilpivirine) bound to RTs that were selected and analyzed
in this study.
Table 1. List of RT···NNRTI complexes with X-ray crystallographically
determined structures
NNRTI PDB ID Mutation on P66 Resolution (Å) Reference
Etravirine 3MEC - 2.30 [21]
Etravirine 3MED K103N 2.50 [21]
Rilpivirine 3MEE - 2.40 [21]
Rilpivirine 3MEG K103N 2.80 [21]
Rilpivirine 3BGR K103N/Y181C 2.10 [21]
Rilpivirine 2ZE2 K103N /L100I 2.90 [21]
For all the calculations considered in this study, the atomic
coordinates of non-hydrogen atoms in NNRTIs (etravirine and
rilpivirine) and their interacting protein residues were extracted
from the X-ray crystal structures of the complexes. The missing
hydrogen atoms were added and their positions were
determined by ab initio geometry optimization at the HF/6-
31+G* level. During the geometry optimization processes, the
positions of heavy (non-hydrogen) atoms were fixed. All
geometry optimization calculations were carried out using the
Gaussian09 software [23].
Intermolecular Interaction Energies in
the Gas Phase
For a given level of theoretical method, the quality of
quantum mechanical calculation depends on the level of
theory used and the choice of the basis set. For an accurate
description of the intermolecular interactions between ligands
and their surrounding protein residues, the electron
correlation must be taken into consideration. Intermolecular
interactions between neutral molecules are usually dominated
by dispersion interactions [24,25] which is caused by the
mutual correlation of electrons that belong to the interacting
partners. The magnitude of correlation energy can be as high
as the magnitude of the intermolecular interaction itself.
3. Madridge Journal of Novel Drug Research
27Madridge J Nov Drug Res.
ISSN: 2641-5232
Volume 1 • Issue 1 • 1000105
Therefore, the inclusion of electron correlation is of a great
importance for a proper description of non-bonded
interactions in biological systems. The Møller–Plesset
perturbation theory at the second order (MP2) represents a
feasible and popular method that recovers a significant
portion of electron correlations [26]. In our study, pair wise
intermolecular interaction energies, in the gas phase, between
etravirine or rilpivirine and their surrounding protein residues
were calculated by ab initio electronic structure calculations at
the MP2 level combined with the triple-zeta cc-pVTZ
Dunning’s correlation basis set for an adequate treatment of
electron correlation.
The interaction energies between inhibitors and their
interacting protein partners were estimated at the MP2/cc-
pVTZ level using the super molecular approach in which the
interaction energy between the two molecules (e.g. A and B)
is computed as the potential energy difference between the
energy of the interacting dimer EAB
and the energies of the
monomers EA
and EB
:
g
B
g
A
g
AB
g
EEEE −−=∆ int
g
B
g
A
g
AB
g
EEEE −−=∆ int
g
B
g
A
g
AB
g
EEEE −−=int (1)
The basis set superposition error (BSSE) was corrected by
the Boys and Bernardi Counter Poise Method [27]. All
calculations were carried out using the Gaussian09 software
[23].
Free Energies of Solvation
Since all biological processes take place in an aqueous
environment in living organisms, the solvation effect has to be
taken into account in order to obtain a reliable estimate of
binding strengths of the intermolecular interactions in
biological systems. A number of different solvation models
have been developed to deal with this issue. Depending on
the way solvent molecules are treated, these models can be
divided into two main classes: implicit solvation models and
explicit solvent models [28,29]. In explicit solvation models, all
of the interactions in the system are fully described at the
atomic level, which means that all the solvent molecules are
explicitly incorporated in quantum mechanics or molecular
mechanics calculations. Unfortunately, explicit treatment of
solvent molecules when simulating biological systems at the
quantum chemical level is not feasible due to the prohibitively
high computational cost. Instead, a common way to calculate
the free energy of solvation when dealing with biological
systems is using the implicit solvation models. In these models,
the solvent is described as a continuum, a polarizable medium
with a fixed dielectric constant equals to the bulk value for
pure solvent. Here, we employed the implicit solvation model
SM5.42R developed by Truhlar and his coworkers [30,31] at
the HF/6-31+G* level as implemented in the GAMESS-version
11 Apr. 2008 (R1) software package [32] to quantify the free
energy of solvation ΔGsol
of the different species considered in
this study.
The standard-state free energy of solvation ΔGsol
in the
SM5.42R model is composed of two components: the
electrostatic term and the first-solvation-shell (non-
electrostatic) term. When the solute is solvated, the charge
distribution of the solute polarizes the surrounding
homogenous dielectric medium of solvent and subsequently,
the polarized field of the solvent acts back on the solute
electric charge distribution to be self-consistent with the
solvent electric polarization. The electrostatic term includes
solute-solvent favorable interactions, solvent rearrangement
cost as well as the energy cost resulting from the distortion of
solute charge distribution. The first-solvation-shell term
includes contributions arising from cavity creation, dispersion
and change in the solvent structure. Before the protein-NNRTI
complex is formed in solution, both the protein and NNRTI
are solvated and have to lose part of their solvation shells
upon binding which incurs an energy cost commonly referred
to as dehydration energy. For a general reaction of A combines
with B to form the AB complex, the dehydration energy for
the complex formation is given by the following equation:
sol
B
sol
A
sol
ABDeh GGGE ∆−∆−∆=∆ g
B
g
A
g
AB
g
EEEE −−=∆ int
g
B
g
A
g
AB
g
EEEE −−=∆ int (2)
where, ΔGi
sol
= AB, A, B represents the free energies of
solvation for the complex AB, and the monomers A, B,
respectively.
Intermolecular Interaction Energies in
Solution
The binding energy for complex formation in solution was
indirectly obtained as a sum of intermolecular interaction
energies in the gas phase (Equation 1) and the dehydration
energies for the complex formation in solution (Equation. 2)
as follows:
int
aq g
Complex DehE E E∆ = ∆ + ∆ (3)
It is worth noting that a similar scheme was used to
calculate solution phase binding affinities for ligand-protein
complexes previously [33,34,35].
Results and Discussion
Since the main objective of this study is to identify
molecular determinants for molecular recognition of second
generation NNRTIs etravirine and rilpivirine in the wild-type
RT and its mutants, we carefully examined crystal structures of
etravirine or rilpivirine bound to the wild-type HIV-1 RT and
mutant strains that are listed in Table 1. Despite the extensive
experimental efforts on studying the mechanism behind the
persistent potency of the secondary generation NNRTIs
etravirine and rilpivirine against wild-type RT and mutated
viruses, quantum chemical analysis is a very useful tool to
quantify the contributions of the individual amino acids in the
non-nucleoside inhibitor binding pocket (NNIBP) to the
overall binding affinities between these drugs and RTs. The
binding environments of both drugs in the wild-type RT and
mutant strains were systematically examined using the Visual
Molecular Dynamic (VMD) program [36] that is capable of
three-dimensional stereographic display. Based on the 3D
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analysis of the crystal structures of RT···NNRTI complexes,
amino acids residues of RTs that form the binding pockets of
etravirine and rilpivirine were systematically identified.
Subsequently, gas phase intermolecular interaction energies
between these inhibitors and their interacting amino acid
residues were calculated by means of the super molecular
approach at the MP2/cc-pVTZ level, followed by solvation
energy correction based on the implicit solvation model
SM5.42R at the HF/6-31+G* level.
Binding of Etravirine/Rilpivirine to the
Wild-Type HIV-1 RT
Due to the similar structural frames of the second
generation NNRTIs etravirine and rilpivirine, both inhibitors
adopt, to a large extent, very similar binding modes to RTs.
Their interacting protein residues are located in the p66
subunit with the exception of Glu138 which belongs to the
p51 subunit. The following amino acids Gly190, Val106,
Val179, Leu100, Leu234, Pro236, Phe227, Tyr181, Tyr188,
Tyr318, Trp229, His235, Lys101, Lys103, and Glu138 are
located within 4.8 Å of both inhibitors and have the potential,
based on 3-D analysis of structures, to be involved in favorable
interactions with the inhibitors. The only two noticeable
differences are that, etravirine seems to have two additional
favorable interactions with Val189 and a water molecule
(residue number 470 in the p51 subunit). The latter appears to
bridge etravirine to RT enzyme via a mediated hydrogen
bond. In addition, rilpivirine appears to be interacting with
Pro95.
Figure 1 shows stereographic displays of the binding
pockets of etravirine and rilpivirine in the wild-type HIV-1 RT.
Hydrogen bonds are shown as red dotted lines. Based on the
above identification of intermolecular contacts, a high level
quantum chemical analysis was employed to quantify the
magnitude of intermolecular interaction energies between
etravirine and rilpivirine and their interacting protein residues.
Listed in Table 2 and Table 3 are the pair wise intermolecular
interaction energies between etravirine/rilpivirine and the
protein residues calculated at the MP2/cc-pVTZ level in the
gas phase (ΔEMP2
) and after solvation correction (ΔEsol
).
Intermolecular interaction energy calculations after taking
solute-solvent interaction into account yields the complete
picture of interactions in a cellular environment. Therefore,
the interaction energies after solvation correction presented
in this study represents the complete picture of the binding
strength of intermolecular interactions between these drugs
and their interacting residues of RTs. The specific type of non
covalent intermolecular interactions between etravirine/
rilpivirine and amino acids of RT are identified and shown in
parentheses.
Figure 1. Stereo diagrams of the binding pocket of NNRTIs in the wild-type HIV-1 RT:(a) etravirine bound with the wild-type HIV-1 RT based
on the 2.30 Å crystal structure of the complex (3MEC, [21]); and (b) rilpivirine bound with the wild-type HIV-1 RT based on the 2.40 Å crystal
structure of the complex (3MEE,[21]). This plot is generated with the program PyMOL [37].
5. Madridge Journal of Novel Drug Research
29Madridge J Nov Drug Res.
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Volume 1 • Issue 1 • 1000105
Table 2. Pairwise intermolecular interaction energies (in kcal/mol)
between etravirine and residues of the wild-type and the K103N
mutant of HIV-1 RT.
PDB ID: 3MEC
(wild-type)
PDB ID:3MED
(K103N)
Energy
Difference
RT Residue ΔE
g
MP2 ΔEsol RT Residue ΔE
g
MP2 ΔEsol Δ(ΔE)**
Gly190 -0.72 -0.04 Gly190 -0.48 -0.10 0.06
Val106 (CH-π) -1.77 -1.65 Val106 (CH-π) -0.90 -1.40 -0.25
Val179 (CH-π) -1.50 -0.94 Val179 (CH-π) -1.47 -0.86 -0.08
Val189 -1.17 -1.46 Val189 -2.00 -1.95 0.49
Leu100 (CH-π) -5.31 -4.04 Leu100 (CH-π) -5.05 -4.87 0.83
Leu234 (CH-π) -1.90 -5.09 Leu234 (CH-π) -1.12 -4.03 -1.06
Pro236 -3.38 1.37 Pro236 -1.03 0.47 0.90
Phe227 -2.80 -0.64 Phe227 -2.10 -0.17 -0.47
Tyr181 (π-π, CH-π) -4.12 -3.92 Tyr181 (π-π, CH-π) -3.98 -3.20 -0.72
Tyr188 (π-π, CH-π) -4.33 -2.93 Tyr188 (π-π, CH-π) -3.52 -2.71 -0.22
Tyr318 (π-π) -4.01 -2.01 Tyr318 (π-π) -3.77 -2.37 0.36
Trp229 (π-π, CH-π) -7.43 -4.15 Trp229 (π-π, CH-π) -7.17 -4.56 0.41
His235 -4.18 0.86 His235 -4.64 -0.29 1.15
Lys101 (H-bond) 0.59 -2.30 Lys101 (H-bond) -2.38 -3.52 1.22
Lys103 (CH-π) -3.11 -3.32 Asn103(CH-π, NH-π) -5.65 -1.53 -1.79
Glu138* -22.99 -3.11 Glu138* -24.62 -3.56 0.45
H2
O470* -2.01 0.44 - - - -
*residues are located on p51 subunit.
**Δ(ΔEsol) = ΔEsol (3MEC)-ΔEsol (3MED)
Table 3. Pairwise intermolecular interaction energies (in kcal/mol)
between rilpivirine and residues of the wild-type and the K103N
mutant of HIV-1 RT.
PDB ID: 3MEE (wild-type) PDB ID: 3MEG (K103N)
Energy
Differ-
ence
RTResidue ΔE
g
MP2 ΔEsol RTResidue ΔE
g
MP2 ΔEsol Δ(ΔE)**
Gly190 -0.99 -1.19 Gly190 - - -
Val106 (CH-π) -3.07 -3.35 Val106 (CH-π) -2.72 -3.12 -0.23
Val179 (CH-π) -2.71 -2.45 Val179 (CH-π) 0.64 0.56 -3.01
Leu100 (CH-π) -5.10 -3.50 Leu100 (CH-π) -4.81 -3.24 -0.26
Leu234 (CH-π) -2.41 -2.02 Leu234 (CH-π) -2.60 -2.14 0.12
Pro95 -0.14 -0.88 Pro95 -0.03 -0.54 -0.34
Pro236 -0.21 1.40 Pro236 -0.03 1.43 -0.03
Phe227 -1.40 1.28 Phe227 -1.00 1.45 -0.17
Tyr181 (π-π, CH-π) -6.06 -3.98 Tyr181 (π-π, CH-π) -5.71 -3.46 -0.52
Tyr188 (π-π, CH-π) -7.29 -5.43 Tyr188 (π-π, CH-π) -7.87 -5.76 0.33
Tyr318 (π-π) -3.47 -1.95 Tyr318 (π-π) -3.35 -1.89 -0.06
Trp229 (π-π, CH-π) -5.51 -2.61 Trp229 (π-π, CH-π) -5.73 -2.65 0.04
His235 -4.91 -0.12 His235 -4.43 -0.39 0.27
Lys101(H-bond,Cation-π) -6.95 -3.29 Lys101(H-bond,Cation-π) -2.44 2.30 -5.59
Lys103 (Cation-π, CH-π) -7.77 -5.90 Asn103 (CH-π, NH-π) -3.59 -0.39 -5.51
Glu138* -13.24 -2.49 Glu138* -13.94 -1.88 -0.61
*residues are located on p51 subunit.
**Δ(ΔEsol) = ΔEsol (3MEE)-ΔEsol (3MEG)
In the case of binding of etravirine to the wild-type HIV-1
RT, as shown in Table 2, all of the gas phase interaction
energies between etravirine and the residues of RT are
attractive (negative) with the exception of the interaction
energy between etravirine and Lys101 which produced a
repulsive energy (positive). After solvation correction,
intermolecular interaction energies between etravirine and its
binding pocket residues in RT are attractive as indicated by
their negative values. An exception is observed in the case of
the interactions with Pro236 and the water molecules (residue
number 470, p51), which give rise to repulsive interactions
(positive values) after solvation correction. The overall binding
energy between etravirine and the wild-type HIV-1 RT as
calculated in solution and estimated as the total of all the
favorable intermolecular interaction energies between
etravirineanditsbindingpocketresidueinRTis-35.60kcal/mol.
In the case of binding of rilpivirine to the wild-type HIV-1 RT,
as shown in Table 3, all of the gas phase interaction energies
between rilpivirine and the residues of RT are attractive
(negative). After solvation correction, the intermolecular
interaction energies between rilpivirine and its interacting
amino acids of RT remain attractive except with Phe227 and
Pro236 which interact unfavorably as implied by the positive
values of their intermolecular interaction energies with
rilpivirine. The overall binding energy for the binding of
rilpivirine to the wild-type HIV-1 RT predicted in solution and
calculated as the sum of all the attractive interactions between
rilpivirine and its binding pocket residues is -39.16 kcal/mol.
As stated in the method section, prior to complex
formation, both the HIV-1 RT and NNRTI are solvated and as
they approach each other both molecules lose parts of their
solvation shell upon binding to each other, which incurs an
energy cost. Therefore, the interactions energies after
solvation correction is usually lower than gas phase interaction
energies especially for hydrogen bonding interactions,
electrostatic interactions (salt-bridge) and cation-π
interactions. The strengths of hydrophobic types of
interactions such as π-π stacking interactions and CH-π
interactions are less affected by solvation correction. As shown
in Table 2 and Table 3, the magnitudes of the intermolecular
interaction energies between etravirine/rilpivirine and RT
after solvation correction are substantially large. This, to a
large extent, can be attributed to the substantial contributions
from π-π interactions and CH-π interactions between
etravirine or rilpivirine and the aromatic and aliphatic residues
of RT. Lys101 forms strong hydrogen bonding interactions
with both inhibitors. Lys103 interacts strongly with etravirine
and rilpivirine in the wild-type RT via CH-π and appears to be
also forming cation-π interaction with rilpivirine.
Binding of Etravirine/Rilpivirine to the
K103 Mutant
The K103N mutation is the most frequent mutation
observed in viruses isolated from patients treated with NNRTIs
[38,39]. It has been found that the K103N single point
mutation is sufficient to confer high level of resistance to the
first generation NNRTIs evirapine and efavirenz, reducing
their susceptibility by 46 and 19-fold, respectively [40,41]. The
second-generation NNRTIs etravirine and rilpivirine, on the
other hand, show good profiles of activity against the single
point K103N mutant, which allow them to retain potency
against this mutant virus [42,43]. To understand the molecular
basis of high binding affinities between etravirine/rilpivirine
and K103N RT, we have quantitatively analyzed binding
pockets of both drugs in the K103N RT mutant.
Following the same procedure as before, the intermolecular
interactions between etravirine/rilpivirine and residues of K103N
RT were energetically analyzed. Figure 2 shows the stereographic
displays of etravirine and rilpivirine binding pockets in the K103N
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mutant. Table 2 and Table 3 list the resulting intermolecular
interaction energies in the gas phase (ΔEMP2
) and after solvation
correction (ΔEsol
) between etravirine and rilpivirine and residues
of K103N mutant. Table 2 also presents a pair wise comparison of
the intermolecular interaction energies between etravirine and
residues of K103N mutant RT with those between etravirine and
the wild-type RT residues. It can be seen that most residues in the
K103N RT mutant maintain strong intermolecular interaction
energies with etravirine in magnitudes that are roughly
comparable to their binding strength with etravirine in the with
wild-type RT. However, mutation of Lys103 to an asparagine
results in a reduction of the solution phase interaction energies
between etravirine and residue #103 from -3.32 kcal/molto -1.53
kcal/mol. Although the hydrogen bond interaction between
etravirine and Lys101 is lost upon the K103N mutation, etravirine
interacts favorably with Asn103 via NH-π and CH-π interactions.
This single point mutation does not have any other noticeable
effect on the intermolecular interactions between etravirine and
the remaining amino acids in the binding pocket of etravirine.
The favorable intermolecular interactions between etravirine and
its binding pocket residues in the K103N mutant add up to a total
of -35.12 kcal/mol stabilization energy. This strong binding
affinity between etravirine and the K103N mutant is comparable
to the binding affinity between etravirine and the wild-type RT.
Intermolecular interaction energies between rilpivirine and
its binding pocket residues in the K103N mutant of HIV-1 RT are
shown in Table 3, in comparison with those between rilpivirine
and the wild-type RT residues. Mutation of lysine residue at
position103toanasparagineresultedinareductionofinteraction
energies from -5.90 kcal/mol to -0.39 kcal/mol, which represents
a stabilization energy loss of -5.51 kcal/mol. Additionally, there
are two significant stabilization energy losses at residue Lys101
(-5.59 kcal/mol stabilization energy loss) and at residue Val179
(-3.01 kcal/mol stabilization energy loss). Based on a careful
examination of the optimized structures, it appears that Lys101 in
wild-type RT interacts with rilpivirine via two hydrogen bonds and
strong cation-π interactions meanwhile there is only one
hydrogen bond formed between the carbonyl group of Lys101
and its adjacent NH group of rilpivirine in the K103N mutant of
RT. In addition, there is change in the position of amino group of
the Lys101 residue upon K103N mutation, which might have
weakened cation-π interactions between Lys101 and rilpivirine. It
was also observed that, the side chain of Val179 change its
position with respect to the rilpivirin ephenyl ring nearby. One of
the CH3
groups of Val179 was pointing to the centroid of the
rilpivirine aromatic ring in the wild-type RT, which results in strong
CH-π interaction. Upon K103N mutation, the side chain of Val179
rotates so that CH3
is no longer pointing toward the centroid of
the aromatic ring of rilpivirine nearby. However, despite these
stabilizationenergylosses,theremainingresiduesoftherilpivirine
binding pocket in K103N RT maintain strong intermolecular
interactions with rilpivirine. The total stabilization energy between
rilpivirine and K103N RT residues is -25.46 kcal/mol. Despite
K103N mutation, both etravirine and rilpivirine maintain strong
interactions with a large number of RT residues, which enables
these inhibitors to overcome drug resistance and retain potency
against the K103N mutant.
(a)
(b)
Figure 2. Stereo diagrams of the binding pocket of NNRTIs in the K103N mutant of HIV-1 RT: (a) etravirine bound with the K103N mutant
based on the 2.50 Å crystal structure of the complex (3MED, [21]; and (b) rilpivirine bound with the K103N mutant based on the 2.80 Å
crystal structure of the complex (3MEG,[21]).This plot is generated with the program PyMOL [37].
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Volume 1 • Issue 1 • 1000105
Binding of Rilpivirine to the K103N/Y181C
double Mutant
The double drug resistance mutations K103N and Y181C
are among the most commonly observed mutations in patients
treated with NNRTIs. The double mutation K103N/Y181C
severely impaired the effectiveness of the first generation
NNRTIs nevirapine and efavirenz. It has been found that
K103N/Y181C double-point mutation reduces nevirapine and
efavirenz potencies by 625 and 1176 fold, respectively [22].
Second generation NNRTIs etravirine and rilpivirine potently
inhibit K103N/Y181C double mutant with EC50
values less than
one nanomolar [44]. Only the X-ray crystal structure of the
K103N/Y181C RT double mutant bound to rilpivirine was
available from the Protein Data Bank (PDB). Therefore, we
were able to conduct a quantitative analysis of the
intermolecular interactions between rilpivirine and its binding
pocket residues in the K103N/Y181C RT double mutant.
Following the same computational procedure as described
earlier, intermolecular interactions between rilpivirine and the
residues of K103N/Y181C RT were systematically analyzed.
Figure 3 shows the stereographic drawing of the rilpivirine
binding pocket in the K103N/Y181C mutant. Potential
hydrogen bonds are shown as red dotted lines.
Figure 3. Stereo diagram of the binding pocket of rilpivirine in the K103N/Y181C double mutant of HIV-1 RTbased on the 2.10 Å crystal
structure of the complex (3BGR,[27] ).This plot is generated with the program PyMOL [37].
Listed in Table 4 are pair wise intermolecular interaction
energies in gas phase (ΔEMP2
) and after solvation correction
(ΔEsol
) between rilpivirine and its interacting residues in the
K103N/Y181C double mutant of HIV-1 RT. For the purpose of
comparison, the interaction energies between rilpivirine and
amino acids of the wild-type are also listed in Table 4.
Comparing the intermolecular interaction energies between
rilpivirine and the K103N/Y181C mutant with those between
rilpivirine and the wild-type RT, we can see that the double-
point mutation K103N/Y181C severely impaired the
intermolecular interactions between rilpivirine and enzyme
residues at position 101 and 103, in a similar manner as in the
case of the K103N mutant. The pair wise intermolecular
interaction energy, in solution, between rilpivirine and Lys101
changes from a favorable -3.29 kcal/mol in wild-type RT to an
unfavorable 1.83 kcal/mol in the K103N/Y181C mutant. This is
a -5.12 kcal/mol stabilization energy loss that can be attributed
to the loss of hydrogen bonding interaction and cation-π
interaction at residue 101 as a result of the K103N/Y181C
mutation. Another great loss of intermolecular interaction
energy is found at residue 103. Upon mutation of Lys103 to
an asparagine, the interaction energy, in solution, changes
from a favorable -5.90 kcal/mol for rilpivirine-Lys103 (in wild-
type) to an unfavorable 1.21 kcal/mol for rilpivirine-Asn103 in
the double mutant RT. This is a -7.11 kcal/mol stabilization
energy loss that can be attributed to the loss of cation-π,
CH-π interactions at residue 103 as a result of the K103N/
Y181C mutations. Additionally, it was found that Asn103
forms a repulsive interaction with rilpivirine after solvation
correction. By examining intermolecular interactions between
rilpivirine and the other residues in the binding pocket, we
found that rilpivirin retains strong interactions with residue
181 after the Y181C mutation. Some other points worth
mentioning here are that, interaction energy after solvation
correction for the rilpivirine-Phe227 pair changes from an
unfavorable 1.28 kcal/molto a favorable -1.65 kcal/mol as a
result of the K103N/Y181C mutation. In addition, there is an
enhancement of interaction energies at residue W229. As can
be seen in Table 4, the interaction energy between rilpivirine
and W229 changes from -2.61 kcal/mol to -4.27 kcal/mol
upon the double mutation. It has been also found that the
binding of rilpivirine to the K103N/Y181C mutant is enhanced
by forming two additional attractive interactions with residues
Tyr183 and a water molecule (residue number 780 in the p51
subunit). The total stabilization energies gained from these
two new interactions are -1.39 and -2.52 kcal/mol, respectively.
The total stabilization energy for the formation of drug-
protein complex between rilpivirine and the K103N/Y181C
double mutant, calculated as the summation of favorable
intermolecular interactions after solvation correction, is -34.07
kcal/mol.
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Table 4. Pairwise intermolecular interaction energies (in kcal/mol)
between rilpivirine and residues of the wild-type and K103N/Y181C
mutant of HIV-1 RT.
PDB ID: 3MEE (wild-type)
PDB ID:3BGR
(K103N/Y181C)
Energy
Difference
RTResidue ΔE
g
MP2 ΔEsol RTResidue ΔE
g
MP2 ΔEsol Δ(ΔE)**
Gly190 -0.99 -1.19 Gly190 -1.01 -0.76 -0.43
Val106 (CH-π) -3.07 -3.35 Val106 (CH-π) -2.41 -2.49 -0.86
Val179 (CH-π) -2.71 -2.45 Val179 (CH-π) -2.90 -2.18 -0.27
Leu100 (CH-π) -5.10 -3.50 Leu100 (CH-π) -4.84 -3.86 0.36
Leu234 (CH-π) -2.41 -2.02 Leu234 (CH-π) -3.91 -3.58 1.56
Pro95 -0.14 -0.88 Pro95 - - 0
Pro236 -0.21 1.40 Pro236 -1.04 0.33 1.07
Phe227 -1.40 1.28 Phe227 (π-π) -3.58 -1.65 2.93
Tyr181 (π-π, CH-π) -6.06 -3.98
Cys181 (CH-π,
S-π)
-4.02 -3.38 -0.60
Tyr188 (π-π, CH-π) -7.29 -5.43
Tyr188 (π-π,
CH-π)
-5.34 -3.33 -2.10
Tyr318 (π-π) -3.47 -1.95 Tyr318 (π-π) -3.24 -2.01 0.06
Trp229 (π-π, CH-π) -5.51 -2.61
Trp229 (π-π,
CH-π)
-6.18 -4.27 1.66
His235 -4.91 -0.12 His235 -4.22 -0.54 0.42
Lys101 (H-bond, Cation-π) -6.95 -3.29 Lys101(H-bond) 0.01 1.83 -5.12
Lys103(Cation-π, CH-π) -7.77 -5.90 Asn103 -2.26 1.21 -7.11
Glu138* -13.24 -2.49 Glu138* -13.39 -2.11 -0.38
Tyr183 -2.56 -1.39 -
H2
O780 (H-bond) -5.52 -2.52 -
*residues located on p51 subunit.
**Δ(ΔEsol) = ΔEsol (3MEE)-ΔEsol (3BGR)
Binding of Rilpivirine to the K103N/L100I
double Mutant
The K103N/L100I double mutation is another common
combination of mutations that has a severe impact on the
effectiveness of the first generation NNRTIs nevirapine and
efavirenz. Although, the K103N/L100I double-point mutation
has a larger effect on the potency of rilpivirine than K103N
and K103N/Y181C mutations, it has been found that second
generation NNRTI rilpivirine retains excellent activity against
the K103N/L100I double mutant virus with an EC50
value of ~
8nM [22]. The availability of X-ray structure of rilpivirine
bound to the K103N/L100I mutant of HIV-1 RT enabled us to
quantify the magnitude of intermolecular interaction energies
between rilpivirine and its binding pocket residues in the
K103N/L100I double mutant. Following a similar manner for
analyzing drug-protein interactions, the intermolecular
interactions between rilpivirine and residues of K103N/L100I
HIV-1 RT were systematically analyzed. Figure 4 shows a
stereographic drawing of the rilpivirine binding pocket in the
K103N/L100I mutant. Hydrogen bond between rilpivirine and
Lys101 is shown as red dotted line.
Table 5 lists the intermolecular interaction energies in gas
phase (ΔEMP2
) and after solvation correction (ΔEsol
) between
rilpivirine and its interacting residues in the K103N/L100I
mutant. For an easy comparison of intermolecular interaction
energies between rilpivirine and the K103N/L100I double
mutant residues with those between rilpivirine and residues
of the wild-type RT, the intermolecular interaction energies
between rilpivirine and its binding pockets residues in both
RTs are listed side by side. It was found that the attractive
interaction between rilpivirine and Lys101 via hydrogen and
cation-π interaction is lost upon the K103N/L100I mutation.
After solvation correction the intermolecular interaction
energy between rilpivirine and Lys101 changes from a
favorable -3.29 kcal/mol (attraction) to an unfavorable 2.38
kcal/mol (repulsion).
Figure 4. Stereo diagram of the binding pocket of rilpivirine in the K103N/L100I double mutant of HIV-1 RT based on the 2.90 Å crystal
structure of the complex (2ZE2,[22]). This plot is generated with the program PyMOL [37].
9. Madridge Journal of Novel Drug Research
33Madridge J Nov Drug Res.
ISSN: 2641-5232
Volume 1 • Issue 1 • 1000105
Table 5. Pairwise intermolecular interaction energies (in kcal/mol)
between rilpivirine and residues of the wild-type and K103N/L100I
mutant of HIV-1 RT.
PDB ID: 3MEE (wild-type) PDB ID: 2ZE2 (K103N/L100I)
Energy
Difference
RTResidue ΔE
g
MP2 ΔEsol RTResidue ΔE
g
MP2 ΔEsol Δ(ΔE)**
Gly190 -0.99 -1.19 Gly190 - - -
Val106 (CH-π) -3.07 -3.35 Val106 (CH-π) -2.80 -2.47 -0.55
Val179 (CH-π) -2.71 -2.45 Val179 (CH-π) -3.05 -2.22 0.6
Leu100 (CH-π) -5.10 -3.50 Ile100 (CH-π) -2.92 -2.04 -0.58
Leu234 (CH-π) -2.41 -2.02 Leu234 (CH-π) -3.71 -3.01 1.69
Pro95 -0.14 -0.88 Pro95 - - -
Pro236 -0.21 1.40 Pro236 -2.25 0.47 3.65
Phe227 -1.40 1.28 Phe227 (π-π) -4.57 -2.38 5.85
Tyr181 (π-π, CH-π) -6.06 -3.98 Tyr181 (π-π, CH-π) -6.75 -4.73 2.77
Tyr188 (π-π, CH-π) -7.29 -5.43 Tyr188 (π-π, CH-π) -6.73 -4.71 1.3
Tyr318 (π-π) -3.47 -1.95 Tyr318 (π-π) -2.36 -0.80 0.41
Trp229 (π-π, CH-π) -5.51 -2.61 Trp229 (π-π) -5.72 -2.71 3.11
His235 -4.91 -0.12 His235 -3.33 0.91 3.21
Lys101(H-bond,Cation-π) -6.95 -3.29 Lys101 (H-bond) 1.11 2.38 -4.4
Lys103 (Cation-π, CH-π) -7.77 -5.90 Asn103 3.79 7.51 -9.69
Glu138* -13.24 -2.49 Glu138* - - -
*residues located on the p51 subunit.
**Δ(ΔEsol) = ΔEsol (3MEE)-ΔEsol (2ZE2)
Another significant stabilization energy loss occurred at
residue 103. The interaction energy changes from a favorable
-3.29 kcal/mol between rilpivirine and Lys103 to an unfavorable
7.51 kcal/mol between rilpivirine and Asn103. This can be
attributed to the loss of cation-π and CH-π interactions at
residue 103 as a consequence of the K103N/L100I double
mutation. A new strong favorable interaction is formed between
rilpivirine and Phe227 in the K103N/L100I mutant. Mutation at
residue 100 in which the leucine residue is replaced by an
isoleucine has a subtle effect on the magnitude of the interaction
energy between rilpivirine and residue 100. Both Leu100 in the
wild-type and Ile100 in the K103N/L100I mutant form strong
CH-π interactions with rilpivirine. The magnitudes of these
intermolecular interaction energies, in solution, are-3.50 kcal/
mol and -2.04 kcal/mol, respectively. Most of the remaining
amino acids in the binding pocket of rilpivirine in the K103N/
L100I mutant form favorable interactions that are comparable
to those between rilpivirine and wild-type RT residues. The total
stabilization energy between rilpivirine and residues of the
K103N/L100I double mutant RT add up to -25.07 kcal/mol. This
strong stabilization energy explains the good activity of
rilpivirine against the K103N/L100I mutant of RT.
Conclusion
In summary, a high level quantum chemical analysis was
carried out to analyze molecular determinants for recognition
between the second generation NNRTIs etravirine and
rilpivirine in HIV-1 RTs. To understand the origin of the potency
of these drugs against wild-type and mutant RTs, the
contributions of the individual amino acid residues in the
NNRTI-binding pocket to the overall binding forces between
etravirine/rilpivirine and both the wild-type RT and some
clinically important mutants RTs were quantum chemically
evaluated. In addition to the large flexibility of these drugs that
allows them to adopt different conformations in response to
the different mutations, non-bonded interaction involving the
aromatic moieties of these drugs are critical for their excellent
activity against the wild-type RT and its mutant strains. The pair
wise intermolecular interaction calculations conducted in our
study have deciphered the molecular level drug-protein
interactions that help these drugs to overcome drug resistance.
It has been discovered that, unlike the first generation of
NNRTIs nevirapine and efavirenz that rely heavily for their
binding to RT on their interactions with Tyr181 and Tyr188,
both etravirine and rilpivirine attain their tight binding to RT
and its mutants by forming strong favorable interactions with a
wide range of their binding pockets residues including the
highly conserved residues Trp229, Leu234, Phe227 and Tyr318.
Therefore, any stabilization energy losses resulting from single
or double point mutations of the non-nucleoside inhibitor
binding pocket (NNIBP) have less effects on etravirine and
rilpivirine potencies. The results of our quantum chemical
calculations presented in this study, enhanced our understanding
of molecular recognition between the second generations
NNRTI etravirine/rilpivirine and RTs, unravelling at the molecular
level the mechanisms that used by these drugs to achieve their
high binding affinities to the clinically relevant mutants of RTs.
It is hoped that the insights gained thorough this rigorous
comparativetheoreticalinvestigationofmoleculardeterminants
for binding of NNRTIs with their targeted wild type and mutant
RTs will lay the foundation for designing the next generation of
NNRTIs that are even more resilient to mutations.
Acknowledgment
It is our great pleasure to acknowledge the Ohio Supercomputer
Centerforagenerousallocationofsupercomputertime.
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