One of the largest families of membrane proteins, the G protein-coupled receptors (GPCRs) has been a very important target of drug discovery as they are involved in having a regulatory role in a variety of signaling pathways at the cellular level in response to external stimuli. Modern in-silico and crystallographic approaches have further made it easier to peep into their structures. In this study, β2 adrenergic receptor (β2AR) has been targeted, and a new ligand molecule using the de-novo approach has been proposed. Using 1-Amino-3-(2,3-dihydro-1H-indol-4-yloxy)-propan-2-ol, the best fitting binding fragments were established with a significant dissociation constant value of 5-7 nanomolar. The flexibility of specific active sites was also investigated, and it was observed that residues 114 (V), 117 (V), 203 (S), 286 (W), and 289 (F) played a crucial role in accommodating ligand for the best binding. Upon examination of the bioavailability parameters, the ligand var9 exhibited significant inhibitory characteristics having lower toxicity values and high drug likeliness properties. Findings certainly hold significance in terms of targeting GPCRs in getting insight into structure-based drug designing and drug discovery.
Poster presented at the Elixir All-Hands Meeting in Lisbon, June 2019. Gives a broad summary of Guide to Pharmacology activities in the last year. Emphasising new tools and our extension into malaria pharmacology.
Poster presented at the Elixir All-Hands Meeting in Lisbon, June 2019. Gives a broad summary of Guide to Pharmacology activities in the last year. Emphasising new tools and our extension into malaria pharmacology.
The IUPHAR/BPS Guide to PHARAMCOLOGY in 2018: new features and updatesGuide to PHARMACOLOGY
2018 update poster for the IUPHAR/BPS Guide to PHARMACOLOGY. Giving details of new features and updates. To be presented at Pharmacology Futures, Edinburgh, May 2018; ELIXIR-All Hands, Berlin, June 2018 and World Congress of Pharmacology, Kyoto, Japan, July 2018
Pharmacokinetic Properties of Biomass-extracted Substances Isolated by Green ...Michal Jablonsky
According to the literature, approximately 41 nutraceutical compounds have been isolated from different types of biomass using green solvents. It is important to collect information on the pharmacokinetic properties of the nutraceutical substances from biomass isolated according to the published papers. The pharmacokinetic properties of the bioactive substances extracted by green solvents, such as the molecular weight, logP, AlogP, H-bond acceptor, H-bond donor, total polar surface area, atom molar refractivity, number of rotatable bonds, number of atoms, rotatable bond count, number of rigid bonds, number of atom rings, and number of H-bonds, were calculated with a drug-likeness tool. In practical terms, the original and most well-known Lipinski's Rule of Five (Ro5) was applied to 28 substances, namely 3-hydroxytyrosol; apigenin; artemisinin; bergapten; bilobalide; biochanin A; caffeic Acid; caffeoylmalic acid; catechins; cinnamic acid; curcumin; daidzei; daidzin; epicatechin; gallic acid; genistein; ginkgolide A; ginkgolide B; levofloxacin; luteolin; naringenin; p-coumaric acid; protocatechuic acid; psoralen; quercetin; trans-ferulic acid; tyrosol, and vanillin.
Stable Drug Designing by Minimizing Drug Protein Interaction Energy Using PSO csandit
Each and every biological function in living organism happens as a result of protein-protein interactions. The diseases are no exception to this. Identifying one or more proteins for a
particular disease and then designing a suitable chemical compound (known as drug) to destroy these proteins has been an interesting topic of research in bio-informatics. In previous methods,drugs were designed using only seven chemical components and were represented as a fixedlength
tree. But in reality, a drug contains many chemical groups collectively known as
pharmacophore. Moreover, the chemical length of the drug cannot be determined before
designing the drug.
In the present work, a Particle Swarm Optimization (PSO) based methodology has been
proposed to find out a suitable drug for a particular disease so that the drug-protein interaction
becomes stable. In the proposed algorithm, the drug is represented as a variable length tree and essential functional groups are arranged in different positions of that drug. Finally, the structure of the drug is obtained and its docking energy is minimized simultaneously. Also, the
orientation of chemical groups in the drug is tested so that it can bind to a particular active site of a target protein and the drug fits well inside the active site of target protein. Here, several inter-molecular forces have been considered for accuracy of the docking energy. Results showthat PSO performs better than the earlier methods.
Each and every biological function in living organism occurs due to protein-protein interactions. The
diseases are no exception to this. Identifying one or more proteins for a particular disease and then
designing a suitable chemical compound (which is known as drug or ligand) to destroy those proteins is a
challenging topic of research in computational biology. In earlier methods, drugs were designed using only
a few chemical components and were represented as a fixed-length tree. But in reality, a drug contains
many chemical groups collectively known as pharmacophore. Moreover, the chemical length of the drug
cannot be determined before designing that drug.
In the present work, a Particle Swarm Optimization (PSO) based methodology has been proposed to find
out a suitable drug for a particular disease so that the drug-target protein interaction energy becomes
minimum. In the proposed algorithm, the drug is represented as a variable length tree and essential
functional groups are arranged in different positions of that drug. Finally, the structure of the drug is
obtained and its docking energy is minimized simultaneously. Also, the orientation of chemical groups in
the drug is tested so that it can bind to a particular active site of a target protein and the drug fits well
inside the active site of target protein. Here, several inter-molecular forces have been considered for
accuracy of the docking energy. Results are demonstrated for three different target proteins both
numerically and pictorially. Results show that PSO performs better than the earlier methods.
Physical and Structural Characterization of Biofield Treated Imidazole Deriva...albertdivis
The Aim of present study was to evaluate the impact of biofield treatment on two imidazole derivatives (i.e., imidazole and 2-methylimidazole) by various analytical methods.
The IOSR Journal of Pharmacy (IOSRPHR) is an open access online & offline peer reviewed international journal, which publishes innovative research papers, reviews, mini-reviews, short communications and notes dealing with Pharmaceutical Sciences( Pharmaceutical Technology, Pharmaceutics, Biopharmaceutics, Pharmacokinetics, Pharmaceutical/Medicinal Chemistry, Computational Chemistry and Molecular Drug Design, Pharmacognosy & Phytochemistry, Pharmacology, Pharmaceutical Analysis, Pharmacy Practice, Clinical and Hospital Pharmacy, Cell Biology, Genomics and Proteomics, Pharmacogenomics, Bioinformatics and Biotechnology of Pharmaceutical Interest........more details on Aim & Scope).
All manuscripts are subject to rapid peer review. Those of high quality (not previously published and not under consideration for publication in another journal) will be published without delay.
Pixe for Elemental Analysis of Domestic Medicinal Plants in Bangladeshijrap
The medicinal plants are a source of biologically important elements which are necessary both for animals
and plants. Present study investigates the concentration of elemental constituents of seven selected
medicinally important plants of Bangladesh, namely Terminalia bellirica, Centella asiatica, Pleurotus
ostreatus, Curcuma longa, Bombax ceiba and Trigonella foenum-graecum. Appropriately desiccated
samples (pellets) of these medicinal plants were bombarded with accelerated proton beam with the help of
3 MV Van de Graff accelerator at accelerator Facilities Division, Atomic Energy Center, Dhaka. Eleven
different elements- P, S, K, Ca, Sc, Ti, V, Mn, Fe, Cd and I were detected by collecting the harvested X-rays
with [Si(Li)] detector. Data collection and analysis were performed using Maestro-32 and GUPIX
software
New nitric oxide releasing indomethacin derivatives with 1,3-thiazolidine-4-o...AlexandruSava6
In this study we present design and synthesis of nineteen new nitric oxide-releasing indomethacin derivatives
with 1,3-thiazolidine-4-one scaffold (NO-IND-TZDs) (6a–s), as a new safer and efficient multi-targets strategy for
inflammatory diseases. The chemical structure of all synthesized derivatives (intermediaries and finals) was
proved by NMR and mass spectroscopic analysis. In order to study the selectivity of NO-IND-TZDs for COX
isoenzymes (COX-1 and COX-2) a molecular docking study was performed using AutoDock 4.2.6 software. Based
on docking results, COX-2 inhibitors were designed and 6o appears as the most selective derivative which
showed an improved selective index compared with indomethacin (IND) and diclofenac (DCF), used as reference
drugs. The biological evaluation of 6a–s, using in vitro assays has included the anti-inflammatory and antioxidant
effects as well as the nitric oxide (NO) release. Referring to the anti-inflammatory effects, the most active
compound was 6i, which was more active than IND and aspirin (ASP) in term of denaturation effect, on bovine
serum albumin (BSA), as indirect assay to predict the anti-inflammatory effect. An appreciable anti-inflammatory
effect, in reference with IND and ASP, was also showed by 6k, 6c, 6q, 6o, 6j, 6d. The antioxidant assay revealed
the compound 6n as the most active, being 100 times more active than IND. The compound 6n showed also the
most increase capacity to release NO, which means is safer in terms of gastro-intestinal side effects. The ADMETox
study revealed also that the NO-IND-TZDs are generally proper for oral administration, having optimal
physico-chemical and ADME properties. We can conclude that the compounds 6i and 6n are promising agents
and could be included in further investigations to study in more detail their pharmaco-toxicological profile
Plausible State-Specific Plans and Recommendations to Avert COVID-19 Communit...Dr Varruchi Sharma
Current article emphasizes upon the strategy to increase the number of tests at the state-level so that majority of the suspected cases could be traced out, isolated and quarantined in order to contain them from becoming a source of infection and coronavirus disease-2019 (COVID-19) dissemination. The objective of the recommended testing is to contain the spread of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. Lessons learnt so far points to the fact that earlier the identification and isolation of infected person, lesser are the chances that it would spread. Considering an example of Maharashtra which has reported cases above 20,000 in the last 7 days with 90,000 tests carried out each day with a test positive report (TPR) of 22%-25%. So, assuming that even if 20% of a particular locality in Maharashtra is infected, then at this rate, we shall be able to isolate only 20,000 each day, while rest of the untraced cases already existing in the locality would pass it on to other people, before being isolated. The only solution to stop this cycle is to outnumber the rate of growth of new cases by increasing the number of tests at a very fast pace. In order to contain the infection, our testing rate has to be much higher than the case growth rate.
The IUPHAR/BPS Guide to PHARAMCOLOGY in 2018: new features and updatesGuide to PHARMACOLOGY
2018 update poster for the IUPHAR/BPS Guide to PHARMACOLOGY. Giving details of new features and updates. To be presented at Pharmacology Futures, Edinburgh, May 2018; ELIXIR-All Hands, Berlin, June 2018 and World Congress of Pharmacology, Kyoto, Japan, July 2018
Pharmacokinetic Properties of Biomass-extracted Substances Isolated by Green ...Michal Jablonsky
According to the literature, approximately 41 nutraceutical compounds have been isolated from different types of biomass using green solvents. It is important to collect information on the pharmacokinetic properties of the nutraceutical substances from biomass isolated according to the published papers. The pharmacokinetic properties of the bioactive substances extracted by green solvents, such as the molecular weight, logP, AlogP, H-bond acceptor, H-bond donor, total polar surface area, atom molar refractivity, number of rotatable bonds, number of atoms, rotatable bond count, number of rigid bonds, number of atom rings, and number of H-bonds, were calculated with a drug-likeness tool. In practical terms, the original and most well-known Lipinski's Rule of Five (Ro5) was applied to 28 substances, namely 3-hydroxytyrosol; apigenin; artemisinin; bergapten; bilobalide; biochanin A; caffeic Acid; caffeoylmalic acid; catechins; cinnamic acid; curcumin; daidzei; daidzin; epicatechin; gallic acid; genistein; ginkgolide A; ginkgolide B; levofloxacin; luteolin; naringenin; p-coumaric acid; protocatechuic acid; psoralen; quercetin; trans-ferulic acid; tyrosol, and vanillin.
Stable Drug Designing by Minimizing Drug Protein Interaction Energy Using PSO csandit
Each and every biological function in living organism happens as a result of protein-protein interactions. The diseases are no exception to this. Identifying one or more proteins for a
particular disease and then designing a suitable chemical compound (known as drug) to destroy these proteins has been an interesting topic of research in bio-informatics. In previous methods,drugs were designed using only seven chemical components and were represented as a fixedlength
tree. But in reality, a drug contains many chemical groups collectively known as
pharmacophore. Moreover, the chemical length of the drug cannot be determined before
designing the drug.
In the present work, a Particle Swarm Optimization (PSO) based methodology has been
proposed to find out a suitable drug for a particular disease so that the drug-protein interaction
becomes stable. In the proposed algorithm, the drug is represented as a variable length tree and essential functional groups are arranged in different positions of that drug. Finally, the structure of the drug is obtained and its docking energy is minimized simultaneously. Also, the
orientation of chemical groups in the drug is tested so that it can bind to a particular active site of a target protein and the drug fits well inside the active site of target protein. Here, several inter-molecular forces have been considered for accuracy of the docking energy. Results showthat PSO performs better than the earlier methods.
Each and every biological function in living organism occurs due to protein-protein interactions. The
diseases are no exception to this. Identifying one or more proteins for a particular disease and then
designing a suitable chemical compound (which is known as drug or ligand) to destroy those proteins is a
challenging topic of research in computational biology. In earlier methods, drugs were designed using only
a few chemical components and were represented as a fixed-length tree. But in reality, a drug contains
many chemical groups collectively known as pharmacophore. Moreover, the chemical length of the drug
cannot be determined before designing that drug.
In the present work, a Particle Swarm Optimization (PSO) based methodology has been proposed to find
out a suitable drug for a particular disease so that the drug-target protein interaction energy becomes
minimum. In the proposed algorithm, the drug is represented as a variable length tree and essential
functional groups are arranged in different positions of that drug. Finally, the structure of the drug is
obtained and its docking energy is minimized simultaneously. Also, the orientation of chemical groups in
the drug is tested so that it can bind to a particular active site of a target protein and the drug fits well
inside the active site of target protein. Here, several inter-molecular forces have been considered for
accuracy of the docking energy. Results are demonstrated for three different target proteins both
numerically and pictorially. Results show that PSO performs better than the earlier methods.
Physical and Structural Characterization of Biofield Treated Imidazole Deriva...albertdivis
The Aim of present study was to evaluate the impact of biofield treatment on two imidazole derivatives (i.e., imidazole and 2-methylimidazole) by various analytical methods.
The IOSR Journal of Pharmacy (IOSRPHR) is an open access online & offline peer reviewed international journal, which publishes innovative research papers, reviews, mini-reviews, short communications and notes dealing with Pharmaceutical Sciences( Pharmaceutical Technology, Pharmaceutics, Biopharmaceutics, Pharmacokinetics, Pharmaceutical/Medicinal Chemistry, Computational Chemistry and Molecular Drug Design, Pharmacognosy & Phytochemistry, Pharmacology, Pharmaceutical Analysis, Pharmacy Practice, Clinical and Hospital Pharmacy, Cell Biology, Genomics and Proteomics, Pharmacogenomics, Bioinformatics and Biotechnology of Pharmaceutical Interest........more details on Aim & Scope).
All manuscripts are subject to rapid peer review. Those of high quality (not previously published and not under consideration for publication in another journal) will be published without delay.
Pixe for Elemental Analysis of Domestic Medicinal Plants in Bangladeshijrap
The medicinal plants are a source of biologically important elements which are necessary both for animals
and plants. Present study investigates the concentration of elemental constituents of seven selected
medicinally important plants of Bangladesh, namely Terminalia bellirica, Centella asiatica, Pleurotus
ostreatus, Curcuma longa, Bombax ceiba and Trigonella foenum-graecum. Appropriately desiccated
samples (pellets) of these medicinal plants were bombarded with accelerated proton beam with the help of
3 MV Van de Graff accelerator at accelerator Facilities Division, Atomic Energy Center, Dhaka. Eleven
different elements- P, S, K, Ca, Sc, Ti, V, Mn, Fe, Cd and I were detected by collecting the harvested X-rays
with [Si(Li)] detector. Data collection and analysis were performed using Maestro-32 and GUPIX
software
New nitric oxide releasing indomethacin derivatives with 1,3-thiazolidine-4-o...AlexandruSava6
In this study we present design and synthesis of nineteen new nitric oxide-releasing indomethacin derivatives
with 1,3-thiazolidine-4-one scaffold (NO-IND-TZDs) (6a–s), as a new safer and efficient multi-targets strategy for
inflammatory diseases. The chemical structure of all synthesized derivatives (intermediaries and finals) was
proved by NMR and mass spectroscopic analysis. In order to study the selectivity of NO-IND-TZDs for COX
isoenzymes (COX-1 and COX-2) a molecular docking study was performed using AutoDock 4.2.6 software. Based
on docking results, COX-2 inhibitors were designed and 6o appears as the most selective derivative which
showed an improved selective index compared with indomethacin (IND) and diclofenac (DCF), used as reference
drugs. The biological evaluation of 6a–s, using in vitro assays has included the anti-inflammatory and antioxidant
effects as well as the nitric oxide (NO) release. Referring to the anti-inflammatory effects, the most active
compound was 6i, which was more active than IND and aspirin (ASP) in term of denaturation effect, on bovine
serum albumin (BSA), as indirect assay to predict the anti-inflammatory effect. An appreciable anti-inflammatory
effect, in reference with IND and ASP, was also showed by 6k, 6c, 6q, 6o, 6j, 6d. The antioxidant assay revealed
the compound 6n as the most active, being 100 times more active than IND. The compound 6n showed also the
most increase capacity to release NO, which means is safer in terms of gastro-intestinal side effects. The ADMETox
study revealed also that the NO-IND-TZDs are generally proper for oral administration, having optimal
physico-chemical and ADME properties. We can conclude that the compounds 6i and 6n are promising agents
and could be included in further investigations to study in more detail their pharmaco-toxicological profile
Plausible State-Specific Plans and Recommendations to Avert COVID-19 Communit...Dr Varruchi Sharma
Current article emphasizes upon the strategy to increase the number of tests at the state-level so that majority of the suspected cases could be traced out, isolated and quarantined in order to contain them from becoming a source of infection and coronavirus disease-2019 (COVID-19) dissemination. The objective of the recommended testing is to contain the spread of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. Lessons learnt so far points to the fact that earlier the identification and isolation of infected person, lesser are the chances that it would spread. Considering an example of Maharashtra which has reported cases above 20,000 in the last 7 days with 90,000 tests carried out each day with a test positive report (TPR) of 22%-25%. So, assuming that even if 20% of a particular locality in Maharashtra is infected, then at this rate, we shall be able to isolate only 20,000 each day, while rest of the untraced cases already existing in the locality would pass it on to other people, before being isolated. The only solution to stop this cycle is to outnumber the rate of growth of new cases by increasing the number of tests at a very fast pace. In order to contain the infection, our testing rate has to be much higher than the case growth rate.
Microbial biotechnology by the participation of microorganism also along with microbial derivatives results in useful products for human welfare. In this process the conversion of natural substances to the processed food is done. The processed substrates can be of diverse range such as enzymes, organic acids, alcohols, polymers, and many more. In reference to human health secondary metabolites are significantly important, such an economically important has deeply benefitted humans by establishing variety of industrial microbial strains. In this chapter we have tried in explaining the microbial role in diverse fields in food production.
Ab-initio density functional and docking studies of α-Santalol molecule deriv...Dr Varruchi Sharma
α-Santalol (a sesquiterpene), an organic compound found in sandalwood was assessed for its reactive potential by computing bond length, Mullikan atomic charges, electrostatic potential surfaces, vibrational frequencies, polarizability, dipole moment and IR spectra with different basis sets implying Hartree Fock and Density functional theory (DFT) Redistribution of charges on α-Santalol was reported to be over a larger range along with the the Bond length values of C32-O39 reportedly higher than the corresponding values of O39-H40 suggestive of its reactivity mainly attributed to hydroxyl group (-OH) attached to C32.Molecular docking studies of α-Santalol with the Monkeypoxgp158 protein further indicate that the designed best probable ligand compound showed significant binding affinity i.e ΔG-8.4Kcal/mole across the binding cleft, suggestive of the therapeutic potential of α-Santalol against monkeypox. Quantum mechanical study of electronic structure, ground state properties and electrostatic potential surface study further supports the reactive sites present in α-Santalol.
Computational Docking Study of the Phytochemical Constituent, Silybin (Silybu...Dr Varruchi Sharma
SARS-CoV-2 is continually evolving with the emergence of new variants with increased viral pathogenicity. The emergence of heavily mutated Omicron (B.1.1.529) with spike protein mutations are known to mediate its higher transmissibility and immune escape that has brought newer challenges for global public health to contain SARS-CoV-2 infection. One has to come up with a therapeutic strategy against the virus so as to effectively contain the infection and spread. Natural phytochemicals are being considered a significant source of bioactive compounds possessing an antiviral therapeutic potential. Being a promising anticancer and chemo-preventive agent, Silybin holds a significant potential to be used as a therapeutic. In the present study, molecular docking of Silybin with Omicron spike protein (7QNW) was carried out. Molecular docking results showed greater stability of Silybin in the active site of the Omicron spike protein with suitable binding mode of interactions. The study reveals that Silybin has the potential to block the host ACE2 receptor-viral spike protein binding; thereby inhibiting the viral entry to human cells. Therefore, Silybin may be further developed as a medication with the ability to effectively combat SARS-CoV-2 Omicron.
Role of plant secondary metabolites as potential antimalarial drugs Dr Varruchi Sharma
Malaria is a global problem affecting a large population without any demarcation between developed and developing world communities. The already approved compounds for the treatment of the disease hold significant efficacy but the emergence of resistant strains and reduced efficacy of drugs against the disease leave the scope for the identification of noval natural products as potential therapeutic agents. There are seven major classes of antiplasmodium agents which are plant secondary metabolites and can be used as a potential antimalarial drugs. In the present review, the focus is on the antimalarial compounds which have been isolated from plants which could be potentially used as antimalarial drugs.
PI3Kinase/AKT/mTOR Pathway in Breast Cancer; Pathogenesis and Prevention with...Dr Varruchi Sharma
The most recurrent and considered second most frequent cause of cancerrelated death in women is the breast cancer worldwide. In breast cancer cases patients are usually diagnosed in the beginning at the curable stage. However, its treatment remains a great clinical challenge. A number of studies have been carried out for the treatment of breast cancer which includes the targeted therapies and increased survival rates in women. Essential PI3K/mTOR signaling pathway activation is observed in most breast cancers. The cell growth and tumor development in this case involves phosphoinositide 3 kinase (PI3K)/ Akt/mammalian target of rapamycin (mTOR) pathway. It has been observed, through preclinical and clinical trials, that there are a number of other inhibitors of PI3K/Akt/mTOR pathway, which either alone or in combination with other agents can be used for treatment of cancer. Pre-clinical studies have confirmed that P13K, Akt and mTOR inhibitors achieve anticancer effects by targeting different levels of the PI3K/Akt/mTOR pathway. This chapter evaluates the role of mTOR along with some of its inhibitors and the PI3K/Akt/mTOR pathway in the pathogenesis and prevention of breast cancer.
BIOINFORMATICS AND ITS APPLICATIONS IN ENVIRONMENTAL SCIENCE AND HEALTH AND I...Dr Varruchi Sharma
Bioinformatics in integration to computational biology is a novel field which applies computer to biology, with which biologists are able to make detailed use of biological data for its advancement. In bioinformatics, the computers are used for the storage followed by the processing and analyzing, along with retrieval of large amounts of biologic and genomic data. In recent years, the field of Bioinformatics is gaining more interest. Earlier, the methodology adopted by the researchers to generate, collect followed by the analysis of various types of scientific data, which is the most time consuming and quite expensive for the work to be carried out. On the other hand with the help of computational tools & techniques, software & databases, one can process a large amount of biological data in a short span such as computer-aided drug designing (CADD). Environment and its protection in today’s word are the most challenging. The problems associated with its protection, planning can be resolved by the best bases of Information technology.
Current Perspective on Dominant Negative Mutations: Trends, Scope and Relevance Dr Varruchi Sharma
Despite the advancements in tools and technologies implicated in identifying and characterizing novel genes, there are still a significant number of unknown function proteins. Moreover, the practices employed in order to characterize such proteins have proven to be a futile exercise so far because of many limitations associated with such traditional approaches. Dominant-negative mutations have shown great promise in this direction as the introduction of mutation in the target protein may abolish the protein function and inhibit the function of the simultaneously expressed wild-type protein. These dominant mutations have broader applications in biological processes to study various proteins in terms of their functional aspects, etiological factors, and mechanism of action, paving the way to diagnose many dreadful diseases, including cancer. Considering these facts, the current review emphasizes utilizing the full potential of such dominant-negative mutations in deciphering protein functions and their broad-spectrum applications in biology
PROBING INTO THE EDIBLE VACCINES: NEWER PARADIGMS, SCOPE AND RELEVANCEDr Varruchi Sharma
Vaccines are proved to be boon for the prevention of infectious diseases and provide acquired immunity against life threatening infections. The lethality of infectious diseases has decreased due to vaccination as it is one of the safe and effective measure to control various infectious diseases. A protein which acts as the vaccine, present in food and consumed as the internal composition of food is known as the edible vaccine. As the name suggests, the term “Edible vaccines” was first used by Charles Arntzen in 1990 and refers to plants that produce vitamins, proteins or other nourishment that act as a vaccine against a certain disease. These vaccines are capable to stimulate the body’s immune system to recognize the antigen. Edible vaccines have been the newer form of vaccines which have the power to cover the risks associated with conventional vaccines. The main mechanism of action of edible vaccines is to activate the systemic and mucosal immunity responses against a foreign disease-causing organism. Edible vaccines are produced by the incorporation of the selected desired genes into the plants and then modified to produce the encoded proteins, providing immunity for certain diseases. Identification, isolation and characterization of a pathogenic antigen is important for making an edible vaccine. At present edible vaccine are developed for various veterinary and human diseases such as cholera, measles, hepatitis and foot and mouth diseases. Current review highlights the importance of edible vaccines which could prove to be cost effective, efficient and safe and would not require refrigeration, making them more accessible to poor people as compared to traditional vaccines.
Oral squamous cell carcinoma (OSCC) has been considered to be the most common malignancy of the head and neck region. OSCC develops as a result of certain genetic and epigenetic variations in the squamous epithelium, which in turn leads to a series of consequences leading to the definitive stage of invasive squamous cell carcinoma. Majority of oral malignancy cases have been associated with specific exposure to certain risk factors such as smoking, smokeless tobacco products, heavy consumption of alcohol, poor oral hygiene, human papilloma virus infection along with other lifestyle factors and dietary changes. There are certain genes named as BIRC2 and BIRC3 belonging to the inhibitors of apoptosis protein (IAP) family which become over-expressed and upregulated during the course of OSCC. The proteins made are pronounced as cIAPs which are inhibitors of specific caspases leading to the suppression of apoptosis induced by a variety of triggering factors.
Current review has brought together all such concrete studies along with diagnostic and therapeutic relevance to OSCC at a single platform so as to understand the etiological factors, mechanism and regulation in oral squamous cell carcinoma. Moreover, the recent emergence of microbiome as a diagnostic and therapeutic target has also been discussed in order to find a sustainable and reliable therapeutic solution to OSCC.
Essence of PTEN: a Broad-Spectrum Therapeutic Target in Cancer Dr Varruchi Sharma
The levels of protein tyrosine phosphorylation within a cell is regulated by protein tyrosine kinases and protein tyrosine phosphatases. These protein tyrosine phosphatases (PTP) can act both as positive and negative regulators during cell cycle progression and signal transduction. Phosphatase activity is shown by Phosphatase and Tensin homolog (PTEN) protein encoded by PTEN gene localized on human chromosome 10. Earlier findings established the role of PTEN as a tumor suppressor in Cowden’s disease, where PTEN mutations resulted in disease outcomes. Subsequent studies found the role of PTEN mutations in various human cancers, making it one of the vastly studied tumor suppressor genes. The current review has been planned to get a deeper insight into the potential role of PTEN in a variety of physiological processes involved in normal development like cell growth, migration, and differentiation along with the factors, regulation, and underlying mechanism
Current Paradigms to Explore the Gut Microbiota Linkage to Neurological Disor...Dr Varruchi Sharma
It has been suggested that an intricate communication link exists between the gut microbiota and the brain and its ability to modulate behaviour of an individual governing homeostasis. Metabolic activity of the microbiota is considered to be relatively constant in healthy individuals, despite diff erences in the composition of microbiota. The metabolites produced by gut microbiota and their homeostatic balance is often perturbed as a result of neurological complications. Therefore, it is of paramount importance to explore the link between gut microbiota and brain function and behaviour through neural, endocrine, and immune pathways. This current review focusses on the impact of altered gut microbiota on brain functions and how microbiome modulation by use of probiotics, prebiotics, and synbiotics might prove benefi cial in the prevention and/or treatment of neurological disorders. It is important to carefully understand the complex mechanisms underlying the gut–brain axis so as to use the gut microbiota as a therapeutic intervention strategy for neurological disorders.
GENDER-BIAS SUSCEPTIBILITY OF CORONA VIRUS DISEASE : PEEPING INTO THE FACTORS...Dr Varruchi Sharma
Recent pandemic of corona virus disease caused by a novel coronavirus SARS-CoV-2 in humans is the third outbreak by this family of viruses, which is reminiscent of the SARS-COV outbreak happened in the year 2003. General characteristics of the novel coronavirus (SARS-CoV-2) especially in regards to the disease susceptibility amongst males and females have been focused providing a better understanding of the coronavirus disease (COVID-19) in males, females and children. A thorough literature search for articles in major databases such as PubMed and Google Scholar etc. has been carried out. COVID-19 has been known to have varied symptoms ranging from mild flu-like symptoms to acute respiratory distress syndrome, multiple organ failure and death. Ageing, genetics, comorbidities and many other associated factors may play a crucial role in predisposing an individual towards COVID-19 disease as there exists chronic inflammation, thrombosis and immune response impairment due to SARS-CoV-2 providing a therapeutic window. Current study emphasizes upon the role of gender in morbidity and mortality in patients with COVID-19 with men higher at risk to COVID-19 than women in terms of mortality despite having the similar prevalence of the disease. The study has been well supported by the data available from the hot-spots affected states from Indian subcontinent. However, current evidence is not sufficient to conclude on the gender-bias susceptibility but certainly men have an edge over women in terms of susceptibility towards COVID-19.
Cancer Chemoprevention by Flavonoids, Dietary Polyphenols and Terpenoids Dr Varruchi Sharma
The world population is aging, and cancer is always considered to be one of the major causes of death all over the globe. The advent of recent drug-targeted therapies undoubtedly is going to reduce the incidence of cancer over the coming years. However, the frequency of occurrence of such chronic diseases like cancer would continue to increase. Therefore, the search for a safer and cost-effective treatment is urgently needed. Phytochemicals found in plants, foods, vegetables, tea, etc. have emerged as proven therapeutic compounds modulating signaling pathways involved in cancer. We carried out a structured search of bibliographic databases for peer-reviewed research literature using the keywords: cancer chemoprevention, flavonoids, dietary polyphenols, terpenoids, bioactive, microbiota. Quality of the retrieved papers and characteristic outcomes of the articles included in the study was assessed by employing standard tools and deductive qualitative content analysis methodology. The development of personalized supplements comprising particular phytochemicals has been the key, especially dealing with chronic inflammatory disorders like cancer. Better understanding at the molecular level explains the influence of phytochemicals on human health, which has been extensively covered through this review. Moreover, the wide collection of dietary polyphenols that has significant properties in reference to human health has been highlighted. Furthermore, the etiology of end products of such phytochemicals, especially on the modulation of gut microbiota and the host-microbial interactions thereof, need to be properly understood. The present study summarizes the chemoprevention and treatment of cancer using the bioactive components, including flavonoids, dietary polyphenols, and terpenoids. Likewise, the effect of dietary polyphenols on the human gut microbiota has been realized more recently. However, more research is needed in this field, especially focused on the communications, interlinks between the gut microbiota and polyphenols with the precise mechanism of action.
MULTIFACETED POTENTIAL OF EICHHORNIA CRASSIPES (WATER HYACINTH) LADENED WITH ...Dr Varruchi Sharma
Being an aquatic weed which is growing dense and widespread across many lakes and water bodies, it is of paramount importance to utilize Eichhornia crassipes (commonly known as water hyacinth) for the benefit of the mankind, especially for its value added and medical properties, such as bio-fuel, biogas, bioremediation and therapeutics. Many of the bird sanctuaries and water-bodies have been drastically invaded by this aquatic weed which is really affecting ecological niche and bird migrations. Several researchers have successfully demonstrated the use of water hyacinth in the bio-remediation and as a potential source of renewable energy. Different heavy and toxic metals showing biomagnifications and therefore creating health hazards, could be remediated by using water hyacinth. The process of decontaminating agro-industrial waste polluted with heavy metals, organic and inorganic pollutants could possibly be done using water hyacinth. Current review focuses towards the efforts to utilize this weed for different value added and therapeutic properties. Furthermore the article emphasizes upon the need to gain more insight into the mechanism with concrete randomized controlled studies to find out the effects of this weed on human health and a sustainable solution to exploit and manage this invasive otherwise harmful weed into a beneficial entity for the mankind.
Disease can occur due to alterations in many physiological processes. A variety of factorsare known to be involved in the progression of cancer, a chronic diseasethat occurs due to permissible proliferative signaling, avoiding growth suppressors, resisting cell death, allowing replicative immortality, induction of angiogenesis, and inducing invasion and metastasis, along with reprogramming of metabolic pathways involved in energy production and avoiding the host immune response for cell destruction. Treatment of such a multifactorial disease has very less cure rate because of the singular agents tried in the past for targeting. Molecular level studies with deeper insight are urgently neededthat focus on the most promising herbal-derived bioactive substances for which thorough research was carried out in the literature in various data-bases such as PUB-MED, MEDLINE, SCOPUS indexed journals etc. to look for systematic reviews of the protocols or data interpretation, natural drug/immunological properties and validation. As immune system plays avery important role in the proliferation or suppression of cancer and other autoimmune diseases, It is the dire need to study the effect of such natural compound on the immune system so that a possible drug target or epitope can be identified for the treatment of such diseases. In nutshell there are many nonclinical in vitro and in vivo studies on herbal medicines which commonly supports the traditional therapeutic claims. It has been seen from the previos studies in literature that the yield and composition of bioactive compounds derived from plants are dependent upon the production source,culturing conditions and extraction protocols.Therefore appropriate optimization conditions would certainly assist the medical and scientific fraternity to accept herbal products as potential candidates for cancer treatment. In this article we explored the different natural products, their immunological effects concerning cancer with no or negligible side effects. However,one has to look for potential herb–drug or herb-epitope interactions and how immune system responds to such drugs.
Role of plant secondary metabolites as potential antimalarial drugsDr Varruchi Sharma
Malaria is a global problem affecting a large population without any demarcation between developed and developing world communities. The already approved compounds for the treatment of the disease hold significant efficacy but the emergence of resistant strains and reduced efficacy of drugs against the disease leave the scope for the identification of noval natural products as potential therapeutic agents. There are seven major classes of antiplasmodium agents which are plant secondary metabolites and can be used as a potential antimalarial drugs. In the present review, the focus is on the antimalarial compounds which have been isolated from plants which could be potentially used as antimalarial drugs.
Targeting Omicron (B.1.1.529) SARS CoV-2 spike protein with selected phytoche...Dr Varruchi Sharma
Severe acute respiratory syndrome coronavirus -2 (S ARS-CoV-2) emerging variants particularly those of concern contain numerous mutations that influence the behavior and transmissibility of the virus and could adversely affect the efficacies of existing coronavirus disease 2019 (COVID-19) vaccines and immunotherapies. The emerging SARS-CoV-2 variants have resulted in different waves of the pandemic within the ongoing COVID-19 pandemic. On 26 November 2021 World Health Organization designated omicron (B.1.1.529) as the fifth variant of concern which was first reported from South Africa on November 24, 2021, and thereafter rapidly spread across the globe owing to its very high transmission rates along with impeding efficacies of existing vaccines and immunotherapies. Omicron contains more than 50 mutations with many mutations (26-32) in spike protein that might be associated with high transmissibility. Natural compounds particularly phytochemicals have been used since ancient times for the treatment of different diseases, and owing to their potent anti-viral properties have also been explored recently against COVID-19. In the present study, molecular docking of nine phytochemicals (Oleocanthal, Tangeritin, Coumarin, Malvidin, Glycitein, Piceatannol, Pinosylnin, Daidzein, and Naringenin) with omicron spike protein (7QNW (electron microscopy, resolution 2.40 Å) was done. The docking study revealed that selected ligands interact with the receptor with binding energy in the range of -6.2 to-7.0 kcal/mol. Pinosylnin showed the highest binding energy of -7.0 kcal/mol which may be used as potential ligands against omicron spike protein. Based on the docking studies, it was suggested that these phytochemicals are potential molecules to be tested against omicron SARS-CoV-2 and can be used to develop effective antiviral drugs.
tecovirimat as a Potential Bioavailable inhibitor against MPXVgp158 establish...Dr Varruchi Sharma
Monkeypox is a zoonotic viral infection caused by monkeypox virus which belongs to the Poxviridae family of genus Orthopoxvirus. Usually the virus transmission happens when the individual comes in contact with the infected person through body fluids, animal lesions, respiratory droplets or through virus contaminated materials. Clinical presentation of the monkeypox has shown significant resemblance to that of smallpox and chickenpox, belonging to the same orthopoxvirus genus but were eradicated during 1980s globally. Monkeypox may lead to a range of medical complications including clinical symptoms like fever, rashes, headaches, back pain, myodynia and swollen lymph nodes. As far as the treatment modalities are concerned,the antiviral therapeutic agents developed for the smallpox treatment, were also permitted to be used for the monkeypox treatment. However, there is no proven treatment for human monkeypox. in the current study, we have focused on designing of a best probable ligand against the target MPXVgp158 (Monkeypox virus protein). Since tecovirimat is an FDA approved compound known as an antipoxviral drug, the study aimed to develop a Monkeypox virus protein MPXVgp158 inhibitor which is bioavailable and biocompatible as well through drug designing using computational tools. Molecular docking (MD) analysis displayed tecovirimat with lesser binding energy, higher non-bonded interaction capability, and more stability against MPXVgp158, with efficient binding mode of interactions. Hence, tecovirimat was adjudged to be the potential candidate against MPXVgp158 inhibition.
How to Make a Field invisible in Odoo 17Celine George
It is possible to hide or invisible some fields in odoo. Commonly using “invisible” attribute in the field definition to invisible the fields. This slide will show how to make a field invisible in odoo 17.
Unit 8 - Information and Communication Technology (Paper I).pdfThiyagu K
This slides describes the basic concepts of ICT, basics of Email, Emerging Technology and Digital Initiatives in Education. This presentations aligns with the UGC Paper I syllabus.
Welcome to TechSoup New Member Orientation and Q&A (May 2024).pdfTechSoup
In this webinar you will learn how your organization can access TechSoup's wide variety of product discount and donation programs. From hardware to software, we'll give you a tour of the tools available to help your nonprofit with productivity, collaboration, financial management, donor tracking, security, and more.
The French Revolution, which began in 1789, was a period of radical social and political upheaval in France. It marked the decline of absolute monarchies, the rise of secular and democratic republics, and the eventual rise of Napoleon Bonaparte. This revolutionary period is crucial in understanding the transition from feudalism to modernity in Europe.
For more information, visit-www.vavaclasses.com
June 3, 2024 Anti-Semitism Letter Sent to MIT President Kornbluth and MIT Cor...Levi Shapiro
Letter from the Congress of the United States regarding Anti-Semitism sent June 3rd to MIT President Sally Kornbluth, MIT Corp Chair, Mark Gorenberg
Dear Dr. Kornbluth and Mr. Gorenberg,
The US House of Representatives is deeply concerned by ongoing and pervasive acts of antisemitic
harassment and intimidation at the Massachusetts Institute of Technology (MIT). Failing to act decisively to ensure a safe learning environment for all students would be a grave dereliction of your responsibilities as President of MIT and Chair of the MIT Corporation.
This Congress will not stand idly by and allow an environment hostile to Jewish students to persist. The House believes that your institution is in violation of Title VI of the Civil Rights Act, and the inability or
unwillingness to rectify this violation through action requires accountability.
Postsecondary education is a unique opportunity for students to learn and have their ideas and beliefs challenged. However, universities receiving hundreds of millions of federal funds annually have denied
students that opportunity and have been hijacked to become venues for the promotion of terrorism, antisemitic harassment and intimidation, unlawful encampments, and in some cases, assaults and riots.
The House of Representatives will not countenance the use of federal funds to indoctrinate students into hateful, antisemitic, anti-American supporters of terrorism. Investigations into campus antisemitism by the Committee on Education and the Workforce and the Committee on Ways and Means have been expanded into a Congress-wide probe across all relevant jurisdictions to address this national crisis. The undersigned Committees will conduct oversight into the use of federal funds at MIT and its learning environment under authorities granted to each Committee.
• The Committee on Education and the Workforce has been investigating your institution since December 7, 2023. The Committee has broad jurisdiction over postsecondary education, including its compliance with Title VI of the Civil Rights Act, campus safety concerns over disruptions to the learning environment, and the awarding of federal student aid under the Higher Education Act.
• The Committee on Oversight and Accountability is investigating the sources of funding and other support flowing to groups espousing pro-Hamas propaganda and engaged in antisemitic harassment and intimidation of students. The Committee on Oversight and Accountability is the principal oversight committee of the US House of Representatives and has broad authority to investigate “any matter” at “any time” under House Rule X.
• The Committee on Ways and Means has been investigating several universities since November 15, 2023, when the Committee held a hearing entitled From Ivory Towers to Dark Corners: Investigating the Nexus Between Antisemitism, Tax-Exempt Universities, and Terror Financing. The Committee followed the hearing with letters to those institutions on January 10, 202
Instructions for Submissions thorugh G- Classroom.pptxJheel Barad
This presentation provides a briefing on how to upload submissions and documents in Google Classroom. It was prepared as part of an orientation for new Sainik School in-service teacher trainees. As a training officer, my goal is to ensure that you are comfortable and proficient with this essential tool for managing assignments and fostering student engagement.
Francesca Gottschalk - How can education support child empowerment.pptxEduSkills OECD
Francesca Gottschalk from the OECD’s Centre for Educational Research and Innovation presents at the Ask an Expert Webinar: How can education support child empowerment?
2024.06.01 Introducing a competency framework for languag learning materials ...Sandy Millin
http://sandymillin.wordpress.com/iateflwebinar2024
Published classroom materials form the basis of syllabuses, drive teacher professional development, and have a potentially huge influence on learners, teachers and education systems. All teachers also create their own materials, whether a few sentences on a blackboard, a highly-structured fully-realised online course, or anything in between. Despite this, the knowledge and skills needed to create effective language learning materials are rarely part of teacher training, and are mostly learnt by trial and error.
Knowledge and skills frameworks, generally called competency frameworks, for ELT teachers, trainers and managers have existed for a few years now. However, until I created one for my MA dissertation, there wasn’t one drawing together what we need to know and do to be able to effectively produce language learning materials.
This webinar will introduce you to my framework, highlighting the key competencies I identified from my research. It will also show how anybody involved in language teaching (any language, not just English!), teacher training, managing schools or developing language learning materials can benefit from using the framework.
Embracing GenAI - A Strategic ImperativePeter Windle
Artificial Intelligence (AI) technologies such as Generative AI, Image Generators and Large Language Models have had a dramatic impact on teaching, learning and assessment over the past 18 months. The most immediate threat AI posed was to Academic Integrity with Higher Education Institutes (HEIs) focusing their efforts on combating the use of GenAI in assessment. Guidelines were developed for staff and students, policies put in place too. Innovative educators have forged paths in the use of Generative AI for teaching, learning and assessments leading to pockets of transformation springing up across HEIs, often with little or no top-down guidance, support or direction.
This Gasta posits a strategic approach to integrating AI into HEIs to prepare staff, students and the curriculum for an evolving world and workplace. We will highlight the advantages of working with these technologies beyond the realm of teaching, learning and assessment by considering prompt engineering skills, industry impact, curriculum changes, and the need for staff upskilling. In contrast, not engaging strategically with Generative AI poses risks, including falling behind peers, missed opportunities and failing to ensure our graduates remain employable. The rapid evolution of AI technologies necessitates a proactive and strategic approach if we are to remain relevant.
Honest Reviews of Tim Han LMA Course Program.pptxtimhan337
Personal development courses are widely available today, with each one promising life-changing outcomes. Tim Han’s Life Mastery Achievers (LMA) Course has drawn a lot of interest. In addition to offering my frank assessment of Success Insider’s LMA Course, this piece examines the course’s effects via a variety of Tim Han LMA course reviews and Success Insider comments.
2. https://doi.org/10.33263/LIANBS101.20632069
https://nanobioletters.com/ 2064
[6-9]. The varying levels of expression of β2adrenoceptors have been reported in a number of
species [10]. Novel drug molecules targeting GPCRs have been designed in the past,
particularly the compounds such as β2 adrenergic receptors that respond to adrenaline and
noradrenaline hormones. There are a variety of targets with reference to the currently available
cardiac and asthma treatment drugs but are having a number of adverse side effects.
Considering the above facts and with the rise in pollution levels and deteriorating environment,
better quality drugs with improved drug likeliness properties are very much required. The
exploration and retrieval of GPCR structures and simultaneously working upon them with
modern drug designing approaches could certainly help in fetching improved drug compounds
[11-12]. Therefore, considering the immense applications of such receptors in a broad range of
disorders, in the present study β2 Adrenergic GPCR was chosen as our potential drug target
[13].
2. Materials and Methods
In-Silico ligand building has been performed using Ligbuilder [9] as we know that
Ligbuilder is based upon a genetic algorithm that is known to construct a library of fragments
on the basis of the target protein and its structural constraints. The coordinates of the seed
molecule (in mol2 format) were used for the formation of a complete ligand simultaneously
satisfying the active site or pocket of the receptor 2RH1. The seed molecule was grown into
the pocket based on Lipinski’s Rule of five [10].
Binding affinities of the populated ligands were estimated using the empirical scoring
function. Using structural libraries, the chemical stability, feasibility, and toxicity of the
molecules were considered. The binding energy of grown ligands was investigated using
HEX[11]. The same program was used to perform the rigid docking and energy of each
receptor-ligand complex and their interactions with Val114, Val117, Ser203, Phe290, Phe289,
and Trp286. The selected binding pocket residues and the potent ligand cluster complex were
visualized using RasMol [12]. The complexes with minimum energy were examined for their
bioavailability, drug likeliness, and toxicity properties using Cheminformatics, Molinspiration
[13] (drug-like properties, and bioactivity of the compounds), and Osiris Property Explorer
(fitness of the ligand) [14].
3. Results and Discussion
In this study, the new molecule using the de-novo approach have been proposed
targeting β2 adrenergic receptors (β2AR). With reference to its 3D structure obtained from
PDB, the recruiting mechanism of amino acids at respective positions i.e., Va114, Va117,
Ser203, Phe290, Trp286, and Phe289, were the prime step of the study. In-Silico ligand
building was performed using Ligbuilder [15-16] in which more than 500,000 molecules were
inhabited by consulting a library of organic fragments, for which we have used 1.2RH1.pdb
(receptor) without heteroatoms and Ligand.mol2 (pre docked ligand, “Carazolol”), including
hydrogen atoms as input file in processing the POCKET. We had an output file as: (1)
2RH1_grid.txt, (2) 2RH1_key_site.pdb, (3) 2RH1_pharmacophore.pdb, (4)
2RH1_pharmacophore.txt, and (5) 2RH1_pocket.txt. The seed molecule which we prepared
was 1-Amino-3-(2,3-dihydro-1H-indol-4-yloxy)-propan-2-ol having the following properties:
Molecular formula: C11H16N2O2, Molecular weight: 208.256 Da, logP:0.044 (Fig. 1). Using “1-
Amino-3-(2,3-dihydro-1H-indol-4-yloxy)-propan-2-ol”, the best fitting binding fragments
3. https://doi.org/10.33263/LIANBS101.20632069
https://nanobioletters.com/ 2065
were established, with a significant dissociation constant value of 5-7 molars. The best
molecule was obtained with docking energy values of 292.15 KJ/mol. The flexibility of specific
active sites was also inspected, and it has been observed that residue 114 (V), 117 (V), 203 (S),
286 (W), and 289 (F) played a crucial role in accommodating ligand for best binding.
Stick view (without Hydrogen)
Figure 1. The seed molecule 1-Amino-3-(2,3-dihydro-1H-indol-4-yloxy)-propan-2-ol).
The coordinates of the seed molecule (in mol2 format) were used further for the
formation of a complete ligand simultaneously satisfying the active site or pocket of the
receptor 2RH1. Using the growing strategy (input used is: Seed.mol2 while the output as (1)
Ligands_2RH1.lig and (2) Population_2RH1.lig), the seed molecules obtained were processed,
generating 10 resultant molecules out of thousands of proposed ligands as shown in Table 1.
Table 1. The resultant ligands were obtained after satisfying the active site or pocket of the receptor 2RH1.
Result
No.
Structure (Ball & Stick view)
Formula
Weight
1. 342 Da
2. 341 Da
3. 340 Da
4. 315 Da
5. 328 Da
4. https://doi.org/10.33263/LIANBS101.20632069
https://nanobioletters.com/ 2066
Result
No.
Structure (Ball & Stick view)
Formula
Weight
6. 340 Da
7. 322 Da
8. 328 Da
9. 318 Da
10.
348 Da
The empirical scoring function was used to estimate the binding affinities of the
populated ligands. Other properties like chemical stability, feasibility, and toxicity were also
considered using structural libraries. After screening, a total of 10 molecules were selected for
further study. The binding energy of grown ligands was investigated using HEX[17]. The same
program performed the rigid docking and energy of each receptor-ligand complex, and their
interactions with Val114, Val117, Ser203, Phe290, Phe289, and Trp286 were further evaluated
with the number of clusters with different energies as an output. Minimum energy clusters were
chosen out of each docked complex. The binding pocket residues and the potent ligand cluster
complex selected were further visualized using RasMol [18]. The ligands showing maximum
interactions and minimal energy were chosen as the potential ligands against β2AR. The best-
docked cluster complexes have been shown in figure 2 where the ligand is shown in violet
while the residues Phe, Trp, Ser, and Val. identified on β2GPCR l, have been shown in red,
blue, yellow, and green colors, respectively. Our ligand binding site has been shown in which
the groove is formed by the seven helices of the β2AR structure.
5. https://doi.org/10.33263/LIANBS101.20632069
https://nanobioletters.com/ 2067
(a) Cluster 1 of var 3:- Docking energy: -285.7 KJ/mol
(b) Cluster 14 of var 6:- Docking energy: -224.09 KJ/mol
(c) Cluster 3 of var 7:-Docking energy: -233.06 KJ/mol
(d) Cluster 1 of var 9:- Docking energy: -292.15 KJ/mol
Figure 2. Four of the best-docked cluster complexes. Ligand is shown in violet while the residues Phe, Trp, Ser,
and Val. identified on β2GPCR l are shown in red, blue, yellow, and green, respectively. The ligand-binding site
is formed by the seven helices of the β2AR structure.
The complexes resulted in minimum energy were further examined for their
bioavailability, drug likeliness, and toxicity properties using Cheminformatics, Molinspiration
[19], and Osiris Property Explorer [20]. We observed through this analysis that 1st
cluster of
result 9 obtained from Hex was having high drug likeliness, higher drug score, and low toxicity
while other parameters were the logP value of this compound as 2.32 with a molecular weight
of 316.45 Da. (Fig. 3). Therefore the molecule appears to be an abiding molecule since it fulfills
6. https://doi.org/10.33263/LIANBS101.20632069
https://nanobioletters.com/ 2068
all the conditions which a ligand must in order to qualify for being used as a potent drug
molecule.
NH
O
O
H
N
H2
CH3
Figure 3. The structure of the potent drug molecule (C19H30N2O2).
After assessing the bioavailability parameters, the var9 (ligand) exhibited significant
β2AR inhibitory characteristics with lower toxicity levels but having high drug likeliness
properties. Var9 (ligand) exhibited the enzyme inhibition values of 0.30, making Var9 (ligand)
to be the best potent antagonistic β2AR ligand molecule.
4. Conclusions
G protein-coupled receptors (GPCRs), one of the largest family of membrane proteins,
have been extremely important targets from the drug discovery perspective. These proteins
have a variety of regulatory roles in cellular signaling pathways. The in-silico modern
approaches and crystallographic analysis have been instrumental in determining their structures
as well. β2 adrenergic receptor (β2AR) was targeted in the present study leading to the
designing of an antagonistic ligand molecule using the de-novo approach. The best-fitting
binding fragments were further established with a significant dissociation constant value of 5-
7 nanomolar. The flexibility of specific active sites was further investigated with the crucial
role played by 114 (V), 117 (V), 203 (S), 286 (W), and 289 (F) residues in accommodating the
ligand for the best binding. The ligand var9 exhibited significant inhibitory characteristics
having lower toxicity values and high drug likeliness properties, making this as a biocompatible
molecule. Further studies are warranted to study this molecule in vitro and in-vivo so as to
establish the therapeutic significance of the molecule. The study certainly holds significance in
targeting GPCRs so as to get mechanistic insight into novel drug discovery and structure-based
drug designing.
Funding
This research received no external funding.
Acknowledgments
We greatly acknowledge Maharishi Markandeshwar (Deemed to be University) Mullana
(Ambala) Haryana, India, for providing the requisite facilities to carry out the said work.
Conflicts of Interest
The authors declare no conflict of interest.
References
1. Lopez-Serra, P.; Esteller, M. DNA methylation-associated silencing of tumor-suppressor microRNAs in
cancer. Oncogene 2012, 31, 1609-1622, https://doi.org/10.1038/onc.2011.354.
2. Varruchi Sharma NB, Anil K. Sharma: In-silico designed and optimized lead inhibiting breast cancer mTOR
FRB domain substrate recruitment mechanism. IPO 21.12.2018.
7. https://doi.org/10.33263/LIANBS101.20632069
https://nanobioletters.com/ 2069
3. Thal, D.M.; Homan, K.T.; Chen, J.; Wu, E.K.; Hinkle, P.M.; Huang, Z.M.; Chuprun, J.K.; Song, J.; Gao, E.;
Cheung, J.Y.; Sklar, L.A.; Koch, W.J.; Tesmer, J.J.G. Paroxetine is a direct inhibitor of g protein-coupled
receptor kinase 2 and increases myocardial contractility. ACS chemical biology 2012, 7, 1830-1839,
https://doi.org/10.1021/cb3003013.
4. Nisoli, E.; Tonello, C.; Landi, M.; Carruba, M.O. Functional studies of the first selective beta 3-adrenergic
receptor antagonist SR 59230A in rat brown adipocytes. Molecular pharmacology 1996, 49, 7-14.
5. Yang SN, Ko HK, Hsiao YH, Su KC, Chang YL, Huang HY, Perng DW, Chung MI. Long-acting muscarinic
antagonist versus long-acting β2 agonist/corticosteroid for moderate to severe chronic obstructive pulmonary
disease patients: Exacerbation risk assessment. J Chin Med Assoc. 2019;82(6):488-494. doi:
10.1097/JCMA.0000000000000114..
6. Sawa, M.; Harada, H. Recent developments in the design of orally bioavailable beta3-adrenergic receptor
agonists. Current medicinal chemistry 2006, 13, 25-37.
7. Sharma VR BN, Sharma AK, Sharma DK, Mishra N.: New and potential therapies for the treatment of Breast
Cancer: An update for oncologists. . CTBCR 2016, 6(1):23-29
8. Sharma V, Sharma AK, Punj V, Priya P: Recent nanotechnological interventions targeting PI3K/Akt/mTOR
pathway: A focus on breast cancer. Semin Cancer Biol 2019, 59:133-146.
9. Sharma VR, Gupta GK, Sharma AK, Batra N, Sharma DK, Joshi A, Sharma AK: PI3K/Akt/mTOR
Intracellular Pathway and Breast Cancer: Factors, Mechanism and Regulation. Curr Pharm Des 2017,
23(11):1633-1638. doi: 10.2174/1381612823666161116125218.
10. January, B.; Seibold, A.; Allal, C.; Whaley, B.S.; Knoll, B.J.; Moore, R.H.; Dickey, B.F.; Barber, R.; Clark,
R.B. Salmeterol‐induced desensitization, internalization and phosphorylation of the human β2‐adrenoceptor.
British journal of pharmacology 1998, 123, 701-711, https://doi.org/10.1038/sj.bjp.0701658.
11. Hothersall, J.D., Jones, A.Y., Dafforn, T.R., Perrior, T. and Chapman, K.L. Releasing the technical
‘shackles’ on GPCR drug discovery: opportunities enabled by detergent-free polymer lipid particle (PoLiPa)
purification. 2020. Drug Discovery Today. https://doi.org/10.1016/j.drudis.2020.08.006.
12. Baker, J.G. The selectivity of β‐adrenoceptor antagonists at the human β1, β2 and β3 adrenoceptors. British
journal of pharmacology 2005, 144, 317-322, https://doi.org/10.1038/sj.bjp.0706048.
13. Bhosale S, Nikte SV, Sengupta D, Joshi M. Differential Dynamics Underlying the Gln27Glu Population
Variant of the β2-Adrenergic Receptor. J Membr Biol. 2019; 252(4-5):499-507. doi: 10.1007/s00232-019-
00093-2.
14. Hudson, B.D.; Hébert, T.E.; Kelly, M.E. Physical and functional interaction between CB1 cannabinoid
receptors and β2‐adrenoceptors. British journal of pharmacology 2010, 160, 627-642,
https://doi.org/10.1111/j.1476-5381.2010.00681.x.
15. Wang, R.; Gao, Y.; Lai, L. LigBuilder: a multi-purpose program for structure-based drug design. Molecular
modeling annual 2000, 6, 498-516, https://doi.org/10.1007/s0089400060498.
16. Yuan Y, Pei J, Lai L. LigBuilder V3: A Multi-Target de novo Drug Design Approach. Front Chem.
2020;28;8:142. doi: 10.3389/fchem.2020.00142.
17. Bagali, S.S.; Gowrishankar, B.S. Molecular Docking of Antipain Inhibitor Using Hex Software.
International Journal of Computational Biology and Bioinformatics 2016, 2, 3-8.
18. Xiaojiang, G.Y.H. Coursewares Of Crystal Structure Made By Rasmol Software [J]. Physics and
Engineering 2006, 3.
19. Othman IMM, Gad-Elkareem MAM, El-Naggar M, Nossier ES, Amr AEE. Novel phthalimide based
analogues: design, synthesis, biological evaluation, and molecular docking studies. J Enzyme Inhib Med
Chem. 2019;34(1):1259-1270. doi:10.1080/14756366.2019.1637861.
20. Sander, T. OSIRIS property explorer. Organic Chemistry Portal 2001.