This document describes a study that used molecular docking to evaluate 9-substituted adenine derivatives as inhibitors of phosphodiesterase type-4 (PDE4) in order to assess their potential anti-inflammatory effects. The study used docking software to predict how well the adenine derivatives could bind to and inhibit the PDE4 enzyme. A total of 22 adenine derivative compounds were analyzed in the docking studies. The results aimed to identify promising lead compounds for further investigation as potential new anti-inflammatory drug candidates.
Solution And Solid Phase Synthesis Publicationadotse
This document describes the solution- and solid-phase synthesis of peptide-substituted thiazolidinediones as potential ligands for peroxisome proliferator-activated receptors (PPARs). Initial studies focused on the low-yielding solution-phase synthesis of two target compounds. Improved yields were obtained using solid-phase synthesis and protecting the thiazolidinedione nitrogen. A small library of nine resin-bound peptide-substituted thiazolidinediones was then synthesized to examine structural features that facilitate PPAR binding and identify new PPAR activators/inhibitors.
Glycolysis is the first stage of cellular respiration where glucose is broken down. It occurs in the cytosol and involves 10 enzyme-catalyzed reactions that convert glucose into two pyruvate molecules, ATP, and NADH. Glycolysis harvests a small amount of energy by producing two ATP and two NADH but requires an initial investment of two ATP. It is an ancient pathway that was the earliest form of energy transfer from organic molecules to ATP.
This document summarizes the design, synthesis, and testing of novel non-covalent thrombin inhibitors featuring P3-heterocycles and P1-bicyclic arginine surrogates. A series of 44 inhibitors (NC1-NC44) were developed using a strategy that included: (1) optimizing P4-aromatic groups for potency and selectivity, (2) linking P4 to P3 heterocycles via short linkers, and (3) surveying diverse weakly basic bicyclic P1 groups to restore potency. Several inhibitors showed potent and selective thrombin inhibition, with some displaying good oral bioavailability in dogs.
This document summarizes the development of a series of 4-substituted-2-aminopyrimidines as inhibitors of c-Jun N-terminal kinases (JNKs). A high-throughput screen identified an initial hit that was a moderately potent JNK1 inhibitor but was rapidly cleared in vitro. The authors synthesized analogs to reduce lipophilicity while maintaining or improving ligand efficiency. They synthesized over 50 compounds and tested them for JNK1 inhibition and cellular activity. The best compound showed improved properties over the initial hit, demonstrating that modifying the alkylamino portion can optimize JNK inhibition and pharmacokinetics.
This document describes the design, synthesis, and evaluation of novel thrombin inhibitors incorporating P3-P4 lactam sulfonamide moieties. The inhibitors were designed to exploit interactions with thrombin's S2 and S3 sites to improve selectivity over related serine proteases. A series of 5-7 membered lactam rings were synthesized and incorporated a P1 argininal group. X-ray crystallography of one inhibitor bound to thrombin confirmed the predicted binding mode. In vitro testing showed several inhibitors had low nanomolar IC50 values against thrombin and good selectivity over trypsin and factor Xa. Overall, the lactam sulfonamides represent a new class of orally bioavailable
His Tag Protein Production and PurificationExpedeon
The study of protein regulation, structure, and function relies heavily on the expression and purification of recombinant proteins. Many recombinant proteins are expressed as fusion proteins, meaning that they contain an affinity / epitope tag. A tag is a short sequence of DNA that codes for a specific amino acid, which is frequently inserted into a target gene at the point of coding for expression at either the N or C terminal of the protein required.
Ribonucleotide reductase converts ribonucleotides to deoxyribonucleotides through reduction of the 2'-OH group on the ribose sugar. It is a heterotetrameric enzyme composed of R1 and R2 subunits, with the R2 subunit containing a tyrosyl free radical required for activity. Thioredoxin provides reducing equivalents to ribonucleotide reductase through thioredoxin reductase and NADPH to allow for continuous reduction of ribonucleotides to the corresponding deoxyribonucleotides needed for DNA synthesis.
Practical 9 protein structure and function (3)Osama Barayan
This document is a lab report on studying protein structure and function using prediction tools and visualization software. It discusses using Rasmol to visualize the 3D structure of rabbit muscle triose phosphate isomerase from its PDB file. Several protein structure prediction servers are also compared, and their predictions for the secondary structure of triose phosphate isomerase are analyzed. The lab report further explores using Rasmol to analyze other protein structures from the PDB, identify heteroatoms and active sites.
Solution And Solid Phase Synthesis Publicationadotse
This document describes the solution- and solid-phase synthesis of peptide-substituted thiazolidinediones as potential ligands for peroxisome proliferator-activated receptors (PPARs). Initial studies focused on the low-yielding solution-phase synthesis of two target compounds. Improved yields were obtained using solid-phase synthesis and protecting the thiazolidinedione nitrogen. A small library of nine resin-bound peptide-substituted thiazolidinediones was then synthesized to examine structural features that facilitate PPAR binding and identify new PPAR activators/inhibitors.
Glycolysis is the first stage of cellular respiration where glucose is broken down. It occurs in the cytosol and involves 10 enzyme-catalyzed reactions that convert glucose into two pyruvate molecules, ATP, and NADH. Glycolysis harvests a small amount of energy by producing two ATP and two NADH but requires an initial investment of two ATP. It is an ancient pathway that was the earliest form of energy transfer from organic molecules to ATP.
This document summarizes the design, synthesis, and testing of novel non-covalent thrombin inhibitors featuring P3-heterocycles and P1-bicyclic arginine surrogates. A series of 44 inhibitors (NC1-NC44) were developed using a strategy that included: (1) optimizing P4-aromatic groups for potency and selectivity, (2) linking P4 to P3 heterocycles via short linkers, and (3) surveying diverse weakly basic bicyclic P1 groups to restore potency. Several inhibitors showed potent and selective thrombin inhibition, with some displaying good oral bioavailability in dogs.
This document summarizes the development of a series of 4-substituted-2-aminopyrimidines as inhibitors of c-Jun N-terminal kinases (JNKs). A high-throughput screen identified an initial hit that was a moderately potent JNK1 inhibitor but was rapidly cleared in vitro. The authors synthesized analogs to reduce lipophilicity while maintaining or improving ligand efficiency. They synthesized over 50 compounds and tested them for JNK1 inhibition and cellular activity. The best compound showed improved properties over the initial hit, demonstrating that modifying the alkylamino portion can optimize JNK inhibition and pharmacokinetics.
This document describes the design, synthesis, and evaluation of novel thrombin inhibitors incorporating P3-P4 lactam sulfonamide moieties. The inhibitors were designed to exploit interactions with thrombin's S2 and S3 sites to improve selectivity over related serine proteases. A series of 5-7 membered lactam rings were synthesized and incorporated a P1 argininal group. X-ray crystallography of one inhibitor bound to thrombin confirmed the predicted binding mode. In vitro testing showed several inhibitors had low nanomolar IC50 values against thrombin and good selectivity over trypsin and factor Xa. Overall, the lactam sulfonamides represent a new class of orally bioavailable
His Tag Protein Production and PurificationExpedeon
The study of protein regulation, structure, and function relies heavily on the expression and purification of recombinant proteins. Many recombinant proteins are expressed as fusion proteins, meaning that they contain an affinity / epitope tag. A tag is a short sequence of DNA that codes for a specific amino acid, which is frequently inserted into a target gene at the point of coding for expression at either the N or C terminal of the protein required.
Ribonucleotide reductase converts ribonucleotides to deoxyribonucleotides through reduction of the 2'-OH group on the ribose sugar. It is a heterotetrameric enzyme composed of R1 and R2 subunits, with the R2 subunit containing a tyrosyl free radical required for activity. Thioredoxin provides reducing equivalents to ribonucleotide reductase through thioredoxin reductase and NADPH to allow for continuous reduction of ribonucleotides to the corresponding deoxyribonucleotides needed for DNA synthesis.
Practical 9 protein structure and function (3)Osama Barayan
This document is a lab report on studying protein structure and function using prediction tools and visualization software. It discusses using Rasmol to visualize the 3D structure of rabbit muscle triose phosphate isomerase from its PDB file. Several protein structure prediction servers are also compared, and their predictions for the secondary structure of triose phosphate isomerase are analyzed. The lab report further explores using Rasmol to analyze other protein structures from the PDB, identify heteroatoms and active sites.
Amino acid analysis and peptide mapping Likhith KLIKHITHK1
Amino Acid Analyzer is specifically configured system optimized for analysis of free amino acids.
PURPOSE:
Detection of presence of Amino acid in variety of biological samples, such as
extracellular and intracellular fluids
plant and animal tissues,
broths, and fruits
beverage juices
Detection of presence of hydrolyzed Amino acid, such as found in
protein, collagen, peptides, and processes foods.
Peptide mapping is an identity test for proteins, especially those
obtained by r-DNA technology. Peptide mapping is a comparative procedure because the information obtained, compared to a Reference Standard or Reference Material similarly treated, confirms the primary structure of the protein, is capable of detecting whether alterations in structure have occurred, and demonstrates process consistency and genetic stability. Peptide mapping refers to the identification of proteins using data from intact peptide masses. It is a powerful test that is capable of identifying single amino acid changes resulting from events such as errors in the reading of complementary DNA (cDNA) sequences or point mutations.
MalA is an α-glucosidase enzyme from Bdellovibrio bacteriovorus that cleaves the bonds of maltose and pNPG. Compounds similar to the hypothetical transition state of hydrolysis, such as acarbose and deoxynojirimycin, strongly inhibit MalA activity. While MalA was purified from E. coli cells, further refinement of the purification protocol is needed to remove contaminating proteins. Future work will use HPLC to quantify MalA reaction products and determine if it exhibits other catalytic activities such as glycosyltransferase or isomerase.
The document discusses arginine methylation, which is a common posttranslational modification that occurs on both nuclear and cytoplasmic proteins. It focuses on the roles of arginine methylation of histone tails by protein arginine methyltransferases (PRMTs) in regulating chromatin function and the histone code. Specifically, it describes the nine PRMT enzymes that catalyze methylation of histone tails, including their classification and substrates. It also discusses potential mechanisms of arginine demethylation and sites of arginine methylation on histone tails.
1. INTRODUCTION
2. WHAT IS A RECEPTOR
3. HISTORY
4. CONCEPT OF CELL SIGNALLING
5. RECEPTOR SUPER FAMILIES
6. GPCRs- SIGNAL TRANSDUCTION & ITS SECOND MESSENGERS
This document discusses various protein modification and signaling pathways in plants. It mentions that protein kinases can phosphorylate enzymes, affecting their activity. Mitogen-activated protein kinase (MAPK) cascades and 14-3-3 proteins are involved in phosphorylation signaling. O-linked N-acetylglucosamine and ubiquitination are other types of post-translational modifications. Lipoxygenase pathways produce oxylipins like jasmonates that regulate defenses against pathogens. Sphingolipids also play a role in resistance responses.
Journal of natural products volume 64 issue, take -- triterpene saponins from...MỐc MOn
This document summarizes research on triterpene saponins isolated from Vietnamese ginseng (Panax vietnamensis) and their ability to protect liver cells. Two new dammarane-type saponins were isolated and identified, along with nine known saponins and one known sapogenin. One of the known saponins, majonoside R2, showed strong protective effects against chemically-induced liver cell death in mice. This demonstrates that the hepatoprotective properties of Vietnamese ginseng are due to dammarane saponins containing an ocotillol-type side chain, characteristic of this plant species.
This document discusses various classes of drugs used to treat inflammation and infection. It outlines different drug targets including enzymes, cytokines, receptors, calcium channels, DNA, protein synthesis, cell membranes, and energy production. Specific drugs are provided that inhibit these targets, such as NSAIDs, corticosteroids, antibiotics, and antifungals.
This document discusses peptide mapping, which involves enzymatically or chemically cleaving a protein into peptides and analyzing the peptides to identify the protein's primary structure. Peptide mapping is used to confirm identity, detect alterations, and ensure consistency for biopharmaceutical characterization. It involves four main steps - selectively cleaving peptide bonds, separating peptides chromatographically (often via RP-HPLC), analyzing and identifying peptides (usually via mass spectrometry), and comparing results to a reference standard to confirm identity. The document provides details on reagents, conditions, and parameters for each step of peptide mapping.
This document summarizes a study that evaluated a glycopeptide esterification method to better estimate sialylation levels and differentiate sialic acid linkages in monoclonal antibodies by MALDI-TOF mass spectrometry. Glycopeptides isolated from tryptic digests of monoclonal antibodies were ethyl esterified. Esterification neutralized sialic acids and decreased metastable fragmentation, allowing more accurate quantification of sialylation. Esterification patterns also enabled differentiation of α2,3 and α2,6 sialic acid linkages. The method was demonstrated to be fast, simple, and effective for monoclonal antibody glycopeptide analysis.
This document summarizes the structure-activity relationships of inhibitors of plasminogen activator inhibitor-1 (PAI-1). PAI-1 regulates several cellular processes and its inhibition may help treat diseases associated with high PAI-1 levels like diabetes and atherosclerosis. The study synthesized sulfonimide- and ester-based inhibitors and evaluated their ability to inhibit PAI-1. Modifying groups like the gallate to protocatechuate or the carbamate side chain altered the inhibitors' potency, with certain modifications improving PAI-1 inhibition. The inhibitors showed IC50 values in the low micromolar range.
The document describes research aimed at discovering new inhibitors of the dopamine transporter (DAT) using computer modeling and virtual screening techniques. Researchers generated a 3D computer model of DAT and identified potential substrate and inhibitor binding pockets, which were validated experimentally. They performed high-throughput virtual screening of over 140,000 compounds using the DAT model and identified pharmacophore constraints within the extracellular vestibule binding pocket. This led to the discovery of 10 hit compounds that were found to displace radiolabeled cocaine analogs from DAT and related monoamine transporters, with nanomolar affinity in some cases. One compound was found to weakly inhibit dopamine uptake itself but reduced the potency of cocaine, representing a first successful use of receptor-based computer
This document was prepared by Afifa Binta Saifuddin and her group members for the assignment purpose for Department of Pharmacy, East West University, Bangladesh. Uploaded by Tousif Azmain.
This document summarizes recent efforts to design small molecule epigenetic modulators that target histone acetyltransferases (HATs), histone deacetylases (HDACs), and histone methyltransferases. It describes the roles of HATs, HDACs, and histone methyltransferases in controlling gene expression through histone and DNA modifications. A handful of HAT inhibitors have been identified, including bisubstrate analogs, natural products, and synthetic small molecules. Inhibitors of HDACs and DNA methyltransferases are more established as epigenetic modulators in cancer treatment. The development of small molecule inhibitors targeting the various writers, erasers, and readers of epigenetic marks offers promise
Bacteria Induced Cryptic Meroterpenoid Pathway in Pathogenic Aspergillus fumi...Debanjan Chatterjee
The document summarizes a presentation on inducing a cryptic meroterpenoid pathway in the pathogenic fungus Aspergillus fumigatus through co-cultivation with the actinomycete Streptomyces rapamycinicus. Co-cultivation led to the activation of a previously silent polyketide synthase gene cluster and the production of novel prenylated polyketides, including Fumicyclines A. Deletion of the polyketide synthase gene confirmed its involvement in biosynthesis. While co-cultivation induced pathway expression, inhibition of histone acetyltransferase did not, suggesting the bacterium alters fungal epigenetic regulation. Understanding secondary metabolism in A. f
This study identified protein arginine methyltransferase 6 (PRMT6) as a coactivator of nuclear factor-kappa B (NF-κB) through three main findings:
1. Transgenic mice overexpressing a fusion of PRMT6 and the estrogen receptor displayed increased levels of interleukin 6 (IL-6), an NF-κB target gene, upon tamoxifen treatment.
2. PRMT6 was found to directly interact with the NF-κB subunit RelA and enhance the transcriptional activity of an NF-κB reporter.
3. PRMT6 was recruited by RelA to selective NF-κB target promoters upon TNF-α stimulation and its overexpression led to increased nuclear accumulation of Rel
Discovery-of-pyrimidyl-5-hydroxamic-acids-as-new-potent-histone-deacetylase-i...Peter ten Holte
This document describes the discovery of new potent histone deacetylase (HDAC) inhibitors containing a pyrimidyl-5-hydroxamic acid structure. A series of these compounds were prepared and tested for HDAC inhibitory activity and antiproliferative effects on cancer cells. The most potent compound contained an amino-2-pyrimidinyl linker and a pyridinyl moiety, inhibiting HDAC activity with an IC50 below 100 nM and reducing cancer cell proliferation in the low micromolar range. Replacing structural elements like the pyrimidinyl ring or changing the heterocyclic ring size generally resulted in lower enzymatic or antiproliferative potency. These results identify amino-2-py
This document summarizes research on the mechanism of drug inhibition and resistance of the influenza A M2 proton channel. Key findings include:
1) Mutational analysis showed that replacing the key residue Asp-44 in the proposed lipid-facing drug binding pocket dramatically reduced drug sensitivity, while replacing Ser-31 with Ala did not affect drug sensitivity, suggesting Ser-31 does not directly bind the drug.
2) The structure of the drug-resistant S31N mutant showed little effect on the channel pore structure but dramatically reduced drug binding to the allosteric lipid-facing pocket, indicating resistance is allosteric rather than from direct pore blocking.
3) Cross-linking studies found an inverse correlation between channel
This document describes research on triplex formation by oligodeoxynucleotides (ODNs) containing 5-methyldeoxycytidine conjugated to spermine (5-Me-dC-N4-(spermine)). The key findings are:
1) ODNs containing 5-Me-dC-N4-(spermine) form stable triplexes at physiological pH (pH 7.3), unlike unmodified ODNs which only form triplexes under acidic conditions.
2) The triplex stability for 5-Me-dC-N4-(spermine) ODNs decreases with decreasing pH, in contrast to unmodified ODNs whose stability increases under acidic conditions
This document summarizes a study investigating novel inhibitors of nicotinamide phosphoribosyltransferase (NAMPT) through screening molecular libraries of potential inhibitors. NAMPT is responsible for replenishing cellular NAD+ pools and forms a homodimer. The study screened compounds for binding at NAMPT's dimerization plane to disrupt dimerization and inhibit activity. A fluorescent assay was developed to measure NAMPT activity by converting its product to a fluorescent derivative. Compounds showing less than 50% activity compared to uninhibited controls were identified as potential NAMPT inhibitors for further investigation as possible chemotherapeutic agents.
Amino acid analysis and peptide mapping Likhith KLIKHITHK1
Amino Acid Analyzer is specifically configured system optimized for analysis of free amino acids.
PURPOSE:
Detection of presence of Amino acid in variety of biological samples, such as
extracellular and intracellular fluids
plant and animal tissues,
broths, and fruits
beverage juices
Detection of presence of hydrolyzed Amino acid, such as found in
protein, collagen, peptides, and processes foods.
Peptide mapping is an identity test for proteins, especially those
obtained by r-DNA technology. Peptide mapping is a comparative procedure because the information obtained, compared to a Reference Standard or Reference Material similarly treated, confirms the primary structure of the protein, is capable of detecting whether alterations in structure have occurred, and demonstrates process consistency and genetic stability. Peptide mapping refers to the identification of proteins using data from intact peptide masses. It is a powerful test that is capable of identifying single amino acid changes resulting from events such as errors in the reading of complementary DNA (cDNA) sequences or point mutations.
MalA is an α-glucosidase enzyme from Bdellovibrio bacteriovorus that cleaves the bonds of maltose and pNPG. Compounds similar to the hypothetical transition state of hydrolysis, such as acarbose and deoxynojirimycin, strongly inhibit MalA activity. While MalA was purified from E. coli cells, further refinement of the purification protocol is needed to remove contaminating proteins. Future work will use HPLC to quantify MalA reaction products and determine if it exhibits other catalytic activities such as glycosyltransferase or isomerase.
The document discusses arginine methylation, which is a common posttranslational modification that occurs on both nuclear and cytoplasmic proteins. It focuses on the roles of arginine methylation of histone tails by protein arginine methyltransferases (PRMTs) in regulating chromatin function and the histone code. Specifically, it describes the nine PRMT enzymes that catalyze methylation of histone tails, including their classification and substrates. It also discusses potential mechanisms of arginine demethylation and sites of arginine methylation on histone tails.
1. INTRODUCTION
2. WHAT IS A RECEPTOR
3. HISTORY
4. CONCEPT OF CELL SIGNALLING
5. RECEPTOR SUPER FAMILIES
6. GPCRs- SIGNAL TRANSDUCTION & ITS SECOND MESSENGERS
This document discusses various protein modification and signaling pathways in plants. It mentions that protein kinases can phosphorylate enzymes, affecting their activity. Mitogen-activated protein kinase (MAPK) cascades and 14-3-3 proteins are involved in phosphorylation signaling. O-linked N-acetylglucosamine and ubiquitination are other types of post-translational modifications. Lipoxygenase pathways produce oxylipins like jasmonates that regulate defenses against pathogens. Sphingolipids also play a role in resistance responses.
Journal of natural products volume 64 issue, take -- triterpene saponins from...MỐc MOn
This document summarizes research on triterpene saponins isolated from Vietnamese ginseng (Panax vietnamensis) and their ability to protect liver cells. Two new dammarane-type saponins were isolated and identified, along with nine known saponins and one known sapogenin. One of the known saponins, majonoside R2, showed strong protective effects against chemically-induced liver cell death in mice. This demonstrates that the hepatoprotective properties of Vietnamese ginseng are due to dammarane saponins containing an ocotillol-type side chain, characteristic of this plant species.
This document discusses various classes of drugs used to treat inflammation and infection. It outlines different drug targets including enzymes, cytokines, receptors, calcium channels, DNA, protein synthesis, cell membranes, and energy production. Specific drugs are provided that inhibit these targets, such as NSAIDs, corticosteroids, antibiotics, and antifungals.
This document discusses peptide mapping, which involves enzymatically or chemically cleaving a protein into peptides and analyzing the peptides to identify the protein's primary structure. Peptide mapping is used to confirm identity, detect alterations, and ensure consistency for biopharmaceutical characterization. It involves four main steps - selectively cleaving peptide bonds, separating peptides chromatographically (often via RP-HPLC), analyzing and identifying peptides (usually via mass spectrometry), and comparing results to a reference standard to confirm identity. The document provides details on reagents, conditions, and parameters for each step of peptide mapping.
This document summarizes a study that evaluated a glycopeptide esterification method to better estimate sialylation levels and differentiate sialic acid linkages in monoclonal antibodies by MALDI-TOF mass spectrometry. Glycopeptides isolated from tryptic digests of monoclonal antibodies were ethyl esterified. Esterification neutralized sialic acids and decreased metastable fragmentation, allowing more accurate quantification of sialylation. Esterification patterns also enabled differentiation of α2,3 and α2,6 sialic acid linkages. The method was demonstrated to be fast, simple, and effective for monoclonal antibody glycopeptide analysis.
This document summarizes the structure-activity relationships of inhibitors of plasminogen activator inhibitor-1 (PAI-1). PAI-1 regulates several cellular processes and its inhibition may help treat diseases associated with high PAI-1 levels like diabetes and atherosclerosis. The study synthesized sulfonimide- and ester-based inhibitors and evaluated their ability to inhibit PAI-1. Modifying groups like the gallate to protocatechuate or the carbamate side chain altered the inhibitors' potency, with certain modifications improving PAI-1 inhibition. The inhibitors showed IC50 values in the low micromolar range.
The document describes research aimed at discovering new inhibitors of the dopamine transporter (DAT) using computer modeling and virtual screening techniques. Researchers generated a 3D computer model of DAT and identified potential substrate and inhibitor binding pockets, which were validated experimentally. They performed high-throughput virtual screening of over 140,000 compounds using the DAT model and identified pharmacophore constraints within the extracellular vestibule binding pocket. This led to the discovery of 10 hit compounds that were found to displace radiolabeled cocaine analogs from DAT and related monoamine transporters, with nanomolar affinity in some cases. One compound was found to weakly inhibit dopamine uptake itself but reduced the potency of cocaine, representing a first successful use of receptor-based computer
This document was prepared by Afifa Binta Saifuddin and her group members for the assignment purpose for Department of Pharmacy, East West University, Bangladesh. Uploaded by Tousif Azmain.
This document summarizes recent efforts to design small molecule epigenetic modulators that target histone acetyltransferases (HATs), histone deacetylases (HDACs), and histone methyltransferases. It describes the roles of HATs, HDACs, and histone methyltransferases in controlling gene expression through histone and DNA modifications. A handful of HAT inhibitors have been identified, including bisubstrate analogs, natural products, and synthetic small molecules. Inhibitors of HDACs and DNA methyltransferases are more established as epigenetic modulators in cancer treatment. The development of small molecule inhibitors targeting the various writers, erasers, and readers of epigenetic marks offers promise
Bacteria Induced Cryptic Meroterpenoid Pathway in Pathogenic Aspergillus fumi...Debanjan Chatterjee
The document summarizes a presentation on inducing a cryptic meroterpenoid pathway in the pathogenic fungus Aspergillus fumigatus through co-cultivation with the actinomycete Streptomyces rapamycinicus. Co-cultivation led to the activation of a previously silent polyketide synthase gene cluster and the production of novel prenylated polyketides, including Fumicyclines A. Deletion of the polyketide synthase gene confirmed its involvement in biosynthesis. While co-cultivation induced pathway expression, inhibition of histone acetyltransferase did not, suggesting the bacterium alters fungal epigenetic regulation. Understanding secondary metabolism in A. f
This study identified protein arginine methyltransferase 6 (PRMT6) as a coactivator of nuclear factor-kappa B (NF-κB) through three main findings:
1. Transgenic mice overexpressing a fusion of PRMT6 and the estrogen receptor displayed increased levels of interleukin 6 (IL-6), an NF-κB target gene, upon tamoxifen treatment.
2. PRMT6 was found to directly interact with the NF-κB subunit RelA and enhance the transcriptional activity of an NF-κB reporter.
3. PRMT6 was recruited by RelA to selective NF-κB target promoters upon TNF-α stimulation and its overexpression led to increased nuclear accumulation of Rel
Discovery-of-pyrimidyl-5-hydroxamic-acids-as-new-potent-histone-deacetylase-i...Peter ten Holte
This document describes the discovery of new potent histone deacetylase (HDAC) inhibitors containing a pyrimidyl-5-hydroxamic acid structure. A series of these compounds were prepared and tested for HDAC inhibitory activity and antiproliferative effects on cancer cells. The most potent compound contained an amino-2-pyrimidinyl linker and a pyridinyl moiety, inhibiting HDAC activity with an IC50 below 100 nM and reducing cancer cell proliferation in the low micromolar range. Replacing structural elements like the pyrimidinyl ring or changing the heterocyclic ring size generally resulted in lower enzymatic or antiproliferative potency. These results identify amino-2-py
This document summarizes research on the mechanism of drug inhibition and resistance of the influenza A M2 proton channel. Key findings include:
1) Mutational analysis showed that replacing the key residue Asp-44 in the proposed lipid-facing drug binding pocket dramatically reduced drug sensitivity, while replacing Ser-31 with Ala did not affect drug sensitivity, suggesting Ser-31 does not directly bind the drug.
2) The structure of the drug-resistant S31N mutant showed little effect on the channel pore structure but dramatically reduced drug binding to the allosteric lipid-facing pocket, indicating resistance is allosteric rather than from direct pore blocking.
3) Cross-linking studies found an inverse correlation between channel
This document describes research on triplex formation by oligodeoxynucleotides (ODNs) containing 5-methyldeoxycytidine conjugated to spermine (5-Me-dC-N4-(spermine)). The key findings are:
1) ODNs containing 5-Me-dC-N4-(spermine) form stable triplexes at physiological pH (pH 7.3), unlike unmodified ODNs which only form triplexes under acidic conditions.
2) The triplex stability for 5-Me-dC-N4-(spermine) ODNs decreases with decreasing pH, in contrast to unmodified ODNs whose stability increases under acidic conditions
This document summarizes a study investigating novel inhibitors of nicotinamide phosphoribosyltransferase (NAMPT) through screening molecular libraries of potential inhibitors. NAMPT is responsible for replenishing cellular NAD+ pools and forms a homodimer. The study screened compounds for binding at NAMPT's dimerization plane to disrupt dimerization and inhibit activity. A fluorescent assay was developed to measure NAMPT activity by converting its product to a fluorescent derivative. Compounds showing less than 50% activity compared to uninhibited controls were identified as potential NAMPT inhibitors for further investigation as possible chemotherapeutic agents.
This document discusses P-glycoprotein (P-gp), an ATP-dependent efflux pump found in the cell membranes of many tissues. P-gp pumps many foreign substances, drugs, and toxins out of cells. It plays an important physiological role and contributes to multidrug resistance in cancer cells by transporting chemotherapy drugs out of the cells. The document outlines the structure, mechanism of action, substrates, inhibitors, and approaches to bypassing P-gp efflux, such as using nanocarrier drug delivery systems.
Automated synthesis of phosphorus modified antisense oligodeoxynucleotidesJerry Zon
Personal reflections of my 20-year odyssey during the early stages of the evolution of this now successful field of synthetic DNA and RNA therapeutics.
This document describes the synthesis of novel N-(3-arylprop-2-ynyl)substituted olanzapine derivatives as potential inhibitors of PDE4B (phosphodiesterase 4B). The target compounds were prepared using a Pd/C-mediated coupling reaction between a terminal alkyne derived from olanzapine and various iodoarenes. Some of the synthesized compounds showed promising inhibition of PDE4B in vitro, with one compound exhibiting over 63% inhibition. Docking studies supported the experimental findings. The results indicate that modifying olanzapine by introducing an appropriate 3-arylprop-2-ynyl moiety can convert it into a PDE inhibitor, offering a potential new
This document provides an overview of the schedule and topics for a course on metabolic networks. The course covers various topics related to metabolism, including enzyme assays, mass spectrometry techniques, primary metabolism, glycogen metabolism, metabolic networks in humans, flux analysis, and biochemical databases. Homework discussions are scheduled every other Friday. Guest lecturers will discuss biochemical databases and tools for modeling metabolism on the last two class meetings. The course includes no class on Veteran's Day and Thanksgiving.
The document discusses the effect of substrate concentration on the enzyme catalase. It was hypothesized that increasing the concentration of hydrogen peroxide substrate would increase the rate of catalase activity, measured by decreased time for an enzyme-coated paper circle to rise in a solution. Potato samples containing catalase were placed in hydrogen peroxide solutions of varying concentrations and temperatures to produce oxygen. Results showed less gas was produced at higher inhibitor concentrations, as more enzymes were inhibited, reducing active sites for reaction.
Phosphodiesterase inhibitors; Could they be used for the treatment of COVID 19?Anjela Ahuja
Role and use of phosphodiesterase inhibitors in the treatment of COVID 19. DISCLAIMER: This is only a brief version of research studies conducted. Not to be taken as a piece of medical advice.
This document describes the synthesis and anti-proliferative evaluation of novel mefenamic acid-based indole analogues. A series of analogues were designed and synthesized using a palladium-catalyzed coupling-cyclization reaction between mefenamic acid-derived alkynes and various iodoindoles. The compounds were evaluated for growth inhibition against normal and cancer cell lines. Several analogues showed selective inhibition of oral cancer cells, with one compound (5g) found to be particularly promising as an anti-proliferative agent.
The document discusses crystal structures of phosphodiesterase 4 (PDE4) regulatory domains bound to small molecule inhibitors. It presents seven crystal structures that show the regulatory domain closed across the active site, revealing how PDE4 activity is regulated by controlling access to the active site. This structural insight allowed the authors to design PDE4 allosteric modulators that only partially inhibit cAMP hydrolysis, rather than completely inhibiting activity like existing drugs. The allosteric modulators showed reduced potential for side effects like emesis in cellular and animal studies while maintaining therapeutic effects.
bradykinin receptor antagonist and thrombin inhibitorsBhanuSri28
1) Bradykinin receptor antagonists and thrombin inhibitors were presented. Bradykinin is a 9-amino acid peptide that promotes inflammation by binding to B1 and B2 G protein-coupled receptors.
2) Conformationally constrained bradykinin antagonist peptides were designed to probe the receptor binding site. NMR studies showed the peptides adopt a beta-turn structure when binding.
3) Receptor binding experiments on cloned human receptors showed similar binding affinities, providing insights into antagonist interactions with bradykinin receptors.
A novel class of pyrimido[4,5-b]-1,4-benzoxazepines is described as inhibitors of epidermal growth factor receptor (EGFR) tyrosine kinase. Two compounds display potent EGFR inhibitory activity of less than 1 μM in cellular phosphorylation assays (IC50 0.47–0.69 μM) and are highly selective against a small kinase panel. Structure-activity relationship studies identified substitutions on the aniline ring and benzoxazepine core that improved potency, with meta-bromo and bis-methoxy substitutions yielding the most active compounds. These tricyclic azepine derivatives represent a new scaffold for EGFR kinase inhibitors with desired selectivity.
Peptidomimetics are compounds whose essential elements (pharmacophore) mimic a natural peptide or protein in 3D space and which retain the ability to interact with the biological target and produce the same biological effect.
Peptidomimetics are designed to circumvent some of the problems associated with a natural peptide for example
Stability against proteolysis (duration of activity)
Poor bioavailability.
Receptor selectivity or potency (often can be substantially improved).
Simplified receptor based pharmacophore approach to retrieve potent ptp lar i...rajmaha9
Simplified Receptor Based Pharmacophore Approach to Retrieve Potent PTP-LAR Inhibitors Using Apoenzyme
M. Elizabeth Sobhia*
Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S.
Nagar, Punjab 160062, India
Abstract: The design of biological active compounds from the apoenzyme is still a challenging task. Herein a simple yet efficient technique is reported to generate a receptor based pharmacophore solely using a ligand-free protein crystal structure. Human leukocyte antigen-related phosphatase (PTP-LAR) is an apoenzyme and a receptor like transmembrane phosphatase that has emerged as a drug target for diabetes, obesity and cancer. The prior knowledge of the active residues responsible for the mechanism of action of the protein was used to generate the LUDI interaction map. Then, the complement negative image of the binding site was used to generate the pharmacophore features. A unique strategy was
followed to design a pharmacophore query maintaining crucial interactions with all the active residues, essential for the enzyme inhibition. The same query was used to screen several databases consisting of the Specs, IBS, iniMaybridge, NCI and an in-house PTP inhibitor databases. In order to overcome the common bioavailability problem associated with phosphatases, the hits obtained were filtered by Lipinski’s Rule of Five, SADMET properties and validated by docking studies in Glide and GOLD. These docking studies not only suggest the essential ligand binding interactions but also the binding patterns necessary for the LAR inhibition. The ligand pharmacophore mapping studies further validated the
screened protocol and supported that the final screened molecules, presumably, showed potent inhibitory activity.
Subsequently, these molecules were subjected to Derek toxicity predictions and nine new molecules with different
scaffold were obtained as non-toxic PTP-LAR inhibitors. The present prospective strategy is a powerful technique to
identify potent inhibitors using the protein 3D structure alone and is a valid alternative to other structure-based and
random docking approaches.
The Development of Heterobifunctional Molecules.pdfDoriaFang
More and more heterobifunctional molecules are designed to target non-druggable targets or expand the scope of treatment. This article describes the development of heterobifunctional molecules.
The document is an author query form from a journal for a manuscript submitted by the authors. It lists four queries for the authors to address:
1) It confirms the article is being processed as a regular item, and asks the authors to contact the editor if it belongs to a special issue.
2) It asks the authors to confirm if the author names have been correctly tagged as given names and surnames.
3) It notes one or more sponsor names may have been edited to a standard format and asks the authors to check.
4) It provides the country names of grant sponsors as 'UGC' - 'India' and asks the authors to check and correct if needed.
This document provides an overview of the topics that will be covered in an enzyme assays and metabolism course over several weeks in November and December. The course will cover topics like enzyme assay fundamentals, mass spectrometry techniques, primary metabolism, glycogen metabolism, metabolic networks in humans, flux analysis, and metabolic databases and modeling tools. It includes the reading assignments and discussion sessions for each class. The readings will cover developing effective enzyme assays, factors that influence enzyme activity, coupled enzyme assays and potential errors, and new techniques for measuring enzyme activity and metabolic states.
Introduction to nucleic acid, chemistry of nucleotiides , july 2020enamifat
This document provides an introduction to nucleic acids, their components, and chemistry. It can be summarized as follows:
1. Nucleic acids are high molecular weight polymers composed of nucleotides linked by phosphodiester bonds. The nucleotides contain a pentose sugar, phosphate group, and nitrogenous base.
2. DNA contains deoxyribose and RNA contains ribose. The nitrogenous bases in DNA are adenine, guanine, cytosine, and thymine, while in RNA thymine is replaced by uracil.
3. Nucleotides are the monomers that make up nucleic acids. They contain a nucleoside (pentose sugar + nitrogenous base), and one or more phosphate groups
This document introduces Ayeesha, a 15-year old student who profoundly impacted the author through her insightful questions about magnetism. The author recounts how Ayeesha challenged him with thought-provoking questions that revealed gaps in his own knowledge, despite his years of experience. He was surprised and impressed to discover that Ayeesha had been reading advanced scientific texts in her spare time. This chance encounter led the author to see flaws in the rote memorization-based system of education and view students as more than just numbers. Ayeesha sparked self-reflection and a desire to improve his teaching approach.
The document contains 46 mathematical formulae related to algebra, quadratic equations, arithmetic progressions, geometric progressions, factorials, and binomial expansions. Some key formulae include:
1) (a + b)2 = a2 + 2ab + b2 for expanding a binomial square.
2) The quadratic formula for solving ax2 + bx + c = 0 is x = (-b ± √(b2 - 4ac))/2a.
3) The nth term of an arithmetic progression with first term a and common difference d is an = a + (n - 1)d.
4) The nth term of a geometric progression with first term a and common ratio
Kavi visai e-book realesed by tamilaka kavinjar kalai ilakkiya sangamTamizhmuhil
The document discusses the results of a study analyzing the effects of a new drug on patients with a certain medical condition. The study found that the drug was generally well-tolerated by patients, with mild side effects reported in most cases. Additionally, positive clinical outcomes were observed in many patients, with a significant percentage experiencing improvement in their symptoms. However, the document notes that more research is still needed.
This document provides instructions for making a birdhouse gift basket out of plastic canvas. The basket features two birdhouses - one in hunter green and one in dark brown. It includes cutting instructions, stitching directions to assemble the front and back, and how to attach the roofs, handles, and fence. When completed, the charming basket can hold small plants or gifts and be displayed on a shelf or windowsill.
A cursor is a SELECT statement defined in PL/SQL code that points to an allocated memory area called the context area containing information needed to process rows returned by a query. Cursors are declared, opened to initialize the result set, rows are fetched from the result set into variables, and then the cursor is closed. There are explicit cursors defined and named by the user, and implicit cursors that Oracle handles automatically for DML statements. Cursor attributes provide information like whether a row was found, the number of rows affected, and whether a cursor is open.
The ArthropodEST pipeline is a web-accessible tool developed at Kansas State University that allows users to analyze expressed sequence tags (ESTs). It cleans input sequences, screens for contaminants, clusters ESTs into contigs through assembly, and predicts open reading frames and signal peptides. Users can access analysis results and a summary report through a unique URL sent to their email. The pipeline utilizes freely available bioinformatics software and provides more options for EST analysis than other existing online tools.
FREE A4 Cyber Security Awareness Posters-Social Engineering part 3Data Hops
Free A4 downloadable and printable Cyber Security, Social Engineering Safety and security Training Posters . Promote security awareness in the home or workplace. Lock them Out From training providers datahops.com
Monitoring and Managing Anomaly Detection on OpenShift.pdfTosin Akinosho
Monitoring and Managing Anomaly Detection on OpenShift
Overview
Dive into the world of anomaly detection on edge devices with our comprehensive hands-on tutorial. This SlideShare presentation will guide you through the entire process, from data collection and model training to edge deployment and real-time monitoring. Perfect for those looking to implement robust anomaly detection systems on resource-constrained IoT/edge devices.
Key Topics Covered
1. Introduction to Anomaly Detection
- Understand the fundamentals of anomaly detection and its importance in identifying unusual behavior or failures in systems.
2. Understanding Edge (IoT)
- Learn about edge computing and IoT, and how they enable real-time data processing and decision-making at the source.
3. What is ArgoCD?
- Discover ArgoCD, a declarative, GitOps continuous delivery tool for Kubernetes, and its role in deploying applications on edge devices.
4. Deployment Using ArgoCD for Edge Devices
- Step-by-step guide on deploying anomaly detection models on edge devices using ArgoCD.
5. Introduction to Apache Kafka and S3
- Explore Apache Kafka for real-time data streaming and Amazon S3 for scalable storage solutions.
6. Viewing Kafka Messages in the Data Lake
- Learn how to view and analyze Kafka messages stored in a data lake for better insights.
7. What is Prometheus?
- Get to know Prometheus, an open-source monitoring and alerting toolkit, and its application in monitoring edge devices.
8. Monitoring Application Metrics with Prometheus
- Detailed instructions on setting up Prometheus to monitor the performance and health of your anomaly detection system.
9. What is Camel K?
- Introduction to Camel K, a lightweight integration framework built on Apache Camel, designed for Kubernetes.
10. Configuring Camel K Integrations for Data Pipelines
- Learn how to configure Camel K for seamless data pipeline integrations in your anomaly detection workflow.
11. What is a Jupyter Notebook?
- Overview of Jupyter Notebooks, an open-source web application for creating and sharing documents with live code, equations, visualizations, and narrative text.
12. Jupyter Notebooks with Code Examples
- Hands-on examples and code snippets in Jupyter Notebooks to help you implement and test anomaly detection models.
Main news related to the CCS TSI 2023 (2023/1695)Jakub Marek
An English 🇬🇧 translation of a presentation to the speech I gave about the main changes brought by CCS TSI 2023 at the biggest Czech conference on Communications and signalling systems on Railways, which was held in Clarion Hotel Olomouc from 7th to 9th November 2023 (konferenceszt.cz). Attended by around 500 participants and 200 on-line followers.
The original Czech 🇨🇿 version of the presentation can be found here: https://www.slideshare.net/slideshow/hlavni-novinky-souvisejici-s-ccs-tsi-2023-2023-1695/269688092 .
The videorecording (in Czech) from the presentation is available here: https://youtu.be/WzjJWm4IyPk?si=SImb06tuXGb30BEH .
How to Interpret Trends in the Kalyan Rajdhani Mix Chart.pdfChart Kalyan
A Mix Chart displays historical data of numbers in a graphical or tabular form. The Kalyan Rajdhani Mix Chart specifically shows the results of a sequence of numbers over different periods.
leewayhertz.com-AI in predictive maintenance Use cases technologies benefits ...alexjohnson7307
Predictive maintenance is a proactive approach that anticipates equipment failures before they happen. At the forefront of this innovative strategy is Artificial Intelligence (AI), which brings unprecedented precision and efficiency. AI in predictive maintenance is transforming industries by reducing downtime, minimizing costs, and enhancing productivity.
Skybuffer AI: Advanced Conversational and Generative AI Solution on SAP Busin...Tatiana Kojar
Skybuffer AI, built on the robust SAP Business Technology Platform (SAP BTP), is the latest and most advanced version of our AI development, reaffirming our commitment to delivering top-tier AI solutions. Skybuffer AI harnesses all the innovative capabilities of the SAP BTP in the AI domain, from Conversational AI to cutting-edge Generative AI and Retrieval-Augmented Generation (RAG). It also helps SAP customers safeguard their investments into SAP Conversational AI and ensure a seamless, one-click transition to SAP Business AI.
With Skybuffer AI, various AI models can be integrated into a single communication channel such as Microsoft Teams. This integration empowers business users with insights drawn from SAP backend systems, enterprise documents, and the expansive knowledge of Generative AI. And the best part of it is that it is all managed through our intuitive no-code Action Server interface, requiring no extensive coding knowledge and making the advanced AI accessible to more users.
Driving Business Innovation: Latest Generative AI Advancements & Success StorySafe Software
Are you ready to revolutionize how you handle data? Join us for a webinar where we’ll bring you up to speed with the latest advancements in Generative AI technology and discover how leveraging FME with tools from giants like Google Gemini, Amazon, and Microsoft OpenAI can supercharge your workflow efficiency.
During the hour, we’ll take you through:
Guest Speaker Segment with Hannah Barrington: Dive into the world of dynamic real estate marketing with Hannah, the Marketing Manager at Workspace Group. Hear firsthand how their team generates engaging descriptions for thousands of office units by integrating diverse data sources—from PDF floorplans to web pages—using FME transformers, like OpenAIVisionConnector and AnthropicVisionConnector. This use case will show you how GenAI can streamline content creation for marketing across the board.
Ollama Use Case: Learn how Scenario Specialist Dmitri Bagh has utilized Ollama within FME to input data, create custom models, and enhance security protocols. This segment will include demos to illustrate the full capabilities of FME in AI-driven processes.
Custom AI Models: Discover how to leverage FME to build personalized AI models using your data. Whether it’s populating a model with local data for added security or integrating public AI tools, find out how FME facilitates a versatile and secure approach to AI.
We’ll wrap up with a live Q&A session where you can engage with our experts on your specific use cases, and learn more about optimizing your data workflows with AI.
This webinar is ideal for professionals seeking to harness the power of AI within their data management systems while ensuring high levels of customization and security. Whether you're a novice or an expert, gain actionable insights and strategies to elevate your data processes. Join us to see how FME and AI can revolutionize how you work with data!
Digital Marketing Trends in 2024 | Guide for Staying AheadWask
https://www.wask.co/ebooks/digital-marketing-trends-in-2024
Feeling lost in the digital marketing whirlwind of 2024? Technology is changing, consumer habits are evolving, and staying ahead of the curve feels like a never-ending pursuit. This e-book is your compass. Dive into actionable insights to handle the complexities of modern marketing. From hyper-personalization to the power of user-generated content, learn how to build long-term relationships with your audience and unlock the secrets to success in the ever-shifting digital landscape.
Have you ever been confused by the myriad of choices offered by AWS for hosting a website or an API?
Lambda, Elastic Beanstalk, Lightsail, Amplify, S3 (and more!) can each host websites + APIs. But which one should we choose?
Which one is cheapest? Which one is fastest? Which one will scale to meet our needs?
Join me in this session as we dive into each AWS hosting service to determine which one is best for your scenario and explain why!
Your One-Stop Shop for Python Success: Top 10 US Python Development Providersakankshawande
Simplify your search for a reliable Python development partner! This list presents the top 10 trusted US providers offering comprehensive Python development services, ensuring your project's success from conception to completion.
TrustArc Webinar - 2024 Global Privacy SurveyTrustArc
How does your privacy program stack up against your peers? What challenges are privacy teams tackling and prioritizing in 2024?
In the fifth annual Global Privacy Benchmarks Survey, we asked over 1,800 global privacy professionals and business executives to share their perspectives on the current state of privacy inside and outside of their organizations. This year’s report focused on emerging areas of importance for privacy and compliance professionals, including considerations and implications of Artificial Intelligence (AI) technologies, building brand trust, and different approaches for achieving higher privacy competence scores.
See how organizational priorities and strategic approaches to data security and privacy are evolving around the globe.
This webinar will review:
- The top 10 privacy insights from the fifth annual Global Privacy Benchmarks Survey
- The top challenges for privacy leaders, practitioners, and organizations in 2024
- Key themes to consider in developing and maintaining your privacy program
Let's Integrate MuleSoft RPA, COMPOSER, APM with AWS IDP along with Slackshyamraj55
Discover the seamless integration of RPA (Robotic Process Automation), COMPOSER, and APM with AWS IDP enhanced with Slack notifications. Explore how these technologies converge to streamline workflows, optimize performance, and ensure secure access, all while leveraging the power of AWS IDP and real-time communication via Slack notifications.
Salesforce Integration for Bonterra Impact Management (fka Social Solutions A...Jeffrey Haguewood
Sidekick Solutions uses Bonterra Impact Management (fka Social Solutions Apricot) and automation solutions to integrate data for business workflows.
We believe integration and automation are essential to user experience and the promise of efficient work through technology. Automation is the critical ingredient to realizing that full vision. We develop integration products and services for Bonterra Case Management software to support the deployment of automations for a variety of use cases.
This video focuses on integration of Salesforce with Bonterra Impact Management.
Interested in deploying an integration with Salesforce for Bonterra Impact Management? Contact us at sales@sidekicksolutionsllc.com to discuss next steps.
This presentation provides valuable insights into effective cost-saving techniques on AWS. Learn how to optimize your AWS resources by rightsizing, increasing elasticity, picking the right storage class, and choosing the best pricing model. Additionally, discover essential governance mechanisms to ensure continuous cost efficiency. Whether you are new to AWS or an experienced user, this presentation provides clear and practical tips to help you reduce your cloud costs and get the most out of your budget.
Dandelion Hashtable: beyond billion requests per second on a commodity serverAntonios Katsarakis
This slide deck presents DLHT, a concurrent in-memory hashtable. Despite efforts to optimize hashtables, that go as far as sacrificing core functionality, state-of-the-art designs still incur multiple memory accesses per request and block request processing in three cases. First, most hashtables block while waiting for data to be retrieved from memory. Second, open-addressing designs, which represent the current state-of-the-art, either cannot free index slots on deletes or must block all requests to do so. Third, index resizes block every request until all objects are copied to the new index. Defying folklore wisdom, DLHT forgoes open-addressing and adopts a fully-featured and memory-aware closed-addressing design based on bounded cache-line-chaining. This design offers lock-free index operations and deletes that free slots instantly, (2) completes most requests with a single memory access, (3) utilizes software prefetching to hide memory latencies, and (4) employs a novel non-blocking and parallel resizing. In a commodity server and a memory-resident workload, DLHT surpasses 1.6B requests per second and provides 3.5x (12x) the throughput of the state-of-the-art closed-addressing (open-addressing) resizable hashtable on Gets (Deletes).
Dandelion Hashtable: beyond billion requests per second on a commodity server
9 sub adenine derivatives-janagi
1. Molecular Docking Studies of 9-Substituted
Adenine Derivatives As Selective
Phosphodiesterase Type-4 Inhibitors
Janagi, T.1, Velmurugan, D2. and Tamizh Muhil, P3.
monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP),
Abstract by the respective PDE subtypes (Smith et al., 2006).
Abnormalities associated with inflammation comprise a large, Selective inhibitors of some PDE families are currently used in clinical
unrelated group of disorders, which underlie a variety of human practice for the treatment of cardiovascular disorders and erectile
diseases. The immune system is often involved with inflammatory dysfunction and other PDE inhibitors are under development for the
disorders, demonstrated in both allergic reactions and some treatment of CNS and inflammatory disorders (Schmitz et al., 2007).
myopathies. An example of the disorder associated with
inflammation includes Asthma, which is a chronic disease of airways Earliest described inhibitors of PDE4, such as rolipram, demonstrated
that is characterized by exacerbations of significant bronchospasm marked anti-inflammatory and bronchodilatory effects in vitro and in
and marked airway inflammation. Cyclic adenosine monophosphate vivo. Unfortunately, the clinical utility of these earlier compounds was
(cAMP) is thought to be associated with inflammatory cell activity: limited by their propensity to elicit various side effects such as nausea
high levels tend to decrease proliferation and cytokine secretion, and gastrointestinal distress. This has led to an extensive effort to
whereas low concentartions have the opposite effect. Since many identify novel PDE4 inhibitors that maintain the anti-inflammatory
phosphodiesterases (PDEs) degrade cAMP, inhibitors of this enzyme activity and bronchodilatory activity of rolipram but with a reduced
decrease inflammatory cell activity. Hence, the PDE enzymes are potential to produce side effects (Dastidar et al., 2009).
used as target for pharmacological inhibition. Inhibitors from the 9- 9-substituted adenine derivatives:
substituted adenine derivatives (6, 9-Disubstituted adenines & 2, 9-
Disubstituted N6 – Methyl adenines) have been studied for their Raboisson et al., described that 9-(2-fluorobenzyl-N6-methyladenine) as
inhibitory activity against PDE4 using docking softwares GoldTM a potent anticonvulsant and they found that several 9-substituted adenine
(CCDC software ltd, UK) and GlideTM (Schrödinger®, USA). derivatives elicited a concentration-dependent inhibiton of the TNF-α
Virtual Screening has been done for all these inhibitors and the release from mononuclear cells. They found the fact that this series of
ligands were chosen for induced fit docking based on their binding PDE4 inhibitors did not stimulate the in vivo gastric acid secretion in rats
affinity, glide energy and glide score. suggesting that they may produce fewer gastrointestinal side effects than
other PDE4 inhibitors (Raboisson et al., 2003). Hence the current study
Key words: 9-substituted adenine derivatives, 6, 9-Disubstituted deals with the in silico docking analysis of the ligands 9-substituted
adenines, 2, 9-Disubstituted N6 Methyl adenines, Phosphodiesterase adenine derivatives as inhibitors of PDE4 with target PDE4B using
type-4 inhibitors docking softwares and aims to evaluate the anti-inflammatory potential
of these ligands.
Introduction
Materials and Methods
Phosphodiesterases, also known as the cyclic nucleotide
phosphodiesterases (PDEs) comprise a group of enzymes, 11 in number Docking is a method which predicts the preferred orientation of one
(PDE1-PDE11) that degrade the phosphodiester bond in the second molecule to a second when bound to each other to form a stable complex
messenger molecules cAMP and cGMP (Huai et al., 2006). They in three-dimensional space. Docking is imminently important in many
regulate the localization, duration, and amplitude of cyclic nucleotide areas. Specifically, in cellular biology, the function of proteins is a result
signaling within sub cellular domains. PDEs are therefore important of its interaction (i.e. docking) with other proteins as well as other
regulators of signal transduction mediated by these second messenger molecular components (Jain, 2008). Therefore if we could predict how
molecules (Clayton et al., 2004; Omori and Kotera, 2007). In particular, proteins interact (dock) with other molecules we could possibly infer or
Phosphodiesterase type4 (PDE4) is a cAMP specific isoenzyme family inhibit function. The inhibiting function is of particular interest to drug
of PDEs that is predominantly expressed in many inflammaory cells and pharmaceutical companies (Warren et al., 2006).
(Schudt et al., 1995). GOLD is Genetic Optimization for Ligand Docking; it follows a genetic
Phosphodiesterase inhibitor: algorithm for calculating the solutions. It can be used for docking
flexible ligands into protein binding sites. Predicting how a small
A phosphodiesterase inhibitor is a drug which blocks one or more of the molecule will bind to a protein is difficult, and no program can guarantee
five subtypes of the enzyme phosphodiesterase, therefore preventing the success. The next best thing therefore is to measure as accurately as
inactivation of the intracellular second messengers, cyclic adenosine possible the reliability of the program, i.e. the chance that it will make a
2. successful prediction in a given instance. For that reason, GOLD has Table 2: 6, 9-Disubstituted Adenines
been tested on a large number of complexes extracted from the Protein
Data Bank.
Glide searches for favorable interactions between one or more typically
small ligand molecules and a larger receptor molecule usually a protein.
Each ligand must be a single molecule, while the receptor may include
Table 1: List Of Databases And Tools Used
Databases & Tools ' H FUSW Q
V L LR From the above basic structure about 22 compounds were
derived with varying R groups (Raboisson et al., 2002)
DrugBank l Target protein structure (PDE4B) was as shown in the table below:
selected from this database using the Compound Molecular R1 R2 R3
details provided for the drug Rolipram. Formula
1 C12H12N6 NH2 H Bn
PDB l Target protein structure PDE4B with 2 C12H11N5O OH H Bn
ligand component AMP was downloaded
3 C16H17N5 Bn
from this database.
4 C16H18N6 Bn
PDBSUM l To identify the active site residues from
5 C13H13N5O OMe H Bn
Ligplot of interactions with AMP.
6 C13H12ClN5 Me H 3-ClBn
Swiss PDB Viewer l To view the target protein structure 7 C15H15N5O2 Me H (MeOCO)(Ph)CH
complexed with AMP and to identify the 8 C15H16N6O Me H (MeNHCO)(Ph)CH
active site residues and export it as 9 C14H15N5O Me H (HOCH2)(Ph)CH
“.pdb” file. 10 C12H11N5 Me H Ph
11 C13H13N5 Me H Ph
Chemsketch l Ligand molecules were drawn and saved 12 C10H15N5 Me H n-Bu
as “.mol” files. 13 C11H15N5 Me H C-Pen
14 C14H15N5 Me H Ph(CH2)2
ArgusLab l To energy minimize the protein structure 15 C15H17N5 Me H Ph(CH2)3
and ligand structures (.mol files from 16 C13H12 ClN5 Me H 4-ClBn
chemsketch) and to export them as 17 C13H12 BrN5 Me H 2-BrBn
“.pdb” files, in order to use in docking. 18 C14H15N5O Me H 2-(MeO)Bn
19 C14H15N5O Me H 4-(MeO)Bn
Gold & Silver l For docking study and viewing the C14H13N5O PhCOCH2
20 Me H
results respectively. 21 C21H21N5 Me H (Ph)2CH(CH)2
22 C20H17N5O Me H 4-(PhCO)PhCH2
Glide l For docking study.
Fig 1: Interaction Of Co-crystal Ligand Docked Into
The Active Site Of Pde4 Receptor Fig 2: Interaction Of Compound 26 Docked Into
The Active Site Of Pde4 Receptor
3. TABLE 3: 2, 9-Disubstituted N6 Methyl Adenines Compound 23 NH CH 3 (N-H ...N)
2.682
N ASN 395:N
9-(2-fluoro F
N
benzyl)-N-methyl- F
N 44.68
2-trifluoromethyl- F N (O-H ...N)
9H-purin-6-amine 2.498
TYR 233:O
C14H11F4 N5 F
Compound 25 H3C
(N-H ...N)
From the above basic structure about 24 compounds were derived NH 2.629
with varying R groups (Raboisson et al., 2002) as shown in the table below: 9-benzyl-2- H3C GLN 443:N
N
isopropyl N6- 45.56
Compound Molecular R1 R2 methyladenine
N
H3C N
Formula N
(O-H ...N) 2.315
C16H19N5 TYR 233:O
23 C14H11F4 N5 CF3 2-FBn
24 C16H19N5 n-Pr Bn
25 C16H19N5 i-Pr Bn
26 C19H23N5 c-Hex Bn Compound 11 H3C (O-H ...N) 2.325
27 C17H21N5 t-Bu Bn 9-benzyl- N
TYR 233:O
N H
28 C21H19N5 PhCH=CH Bn N6-methyl - (N-H ...N)
adenine 2.482
29 C13H14N6 NH2 Bn ASN 395:N
C13H13N5 N N 45.74
30 C15H17N5O Me 2-(MeO)Bn
(N-H ...N)
31 C15H17N5O Me 4-(MeO)Bn N GLN 443:N 2.516
32 C16H19N5O Me 2-(MeO)Ph(CH2)2
(N-H ...N)
33 C12H19N5O2 Me CH3O(CH2)2O(CH2)2 GLN 443:N 2.506
34 C18H23N5 n-Pen Bn Compound 24 NH CH3 (O-H ...N)
35 Ph(CH2)2 2.745
C21H21N5 Bn TYR 233:O
9-benzyl- N
36 C22H23N5 Ph(CH2)3 Bn N6-methyl -2-n-
N
(N-H ...N) 46.13
37 C15H14F3N5O CF3 2-(MeO)Bn propyladenine N
N ASN 395:N 2.555
H3C
38 C17H21N5O n-Pr 2-(MeO)Bn C16H19N5
(N-H ...N)
39 C23H23 N5O n-Pr 4-(PhCO)PhCH2 GLN 443:N 2.389
40 C14H14FN5 Me 2-FBn Compound 38 NH2 (O-H ...N)
41 C13H12IN5 I Bn 2.625
9-(2-methoxy N
TYR 233:O
42 C14H14IN5O I 2-(MeO)Bn N
benzyl)- N6-
43 CH3C = C (N-H ...N)
C16H15N5 Bn methyl -2-n- N
GLN 443:N 2.708 47.47
H3C N
44 C17H17N5O CH3C = C 2-(MeO)Bn propyladenine
45 C17H19N5O CH3CH=CH 2-(MeO)Bn C17H21N5O (N-H ...N)
GLN 443:N 2.558
46 C15H17N5OS CH3S 2-(MeO)Bn O
CH3
Results Compound 8 H
N
CH3
(N-H …O) 2.583
N ASP 392:O
Table 4: Gold Fitness Score And Interactions Of Best Ligands N-{[6- (methyl N
N
amino)-9H-purin- N
(O-H ...N) 2.551 48.50
(Interactions : Hydrogen bonds viewed from Silver – listed for reference ligand 9-yl]methyl}-2- HN
TYR 233:O
O
AMP and all other ligands that have Gold score > AMP i.e. > 44.40) phenyl-acetamide
Bond (N-H ...O) 2.517
Compounds Structures Interactions C15H16N6O TYR 233:O
Distance Gold
(D-H ...A) Between Score Compound 34 H3C NH N O-H ...N) 2.461
Donor& TYR 233:O
Acceptor (Å) 9-benzyl- N6- N
methyl-2-n-pentyl-
N 50.09
Co-crystal (O-H …O) N (N-H ...N) 2.622
2.479 adenine GLN 443:N
Amp ASP 392:O C18H23N5
{2-[(2R, 3S, H3C
4R, 5R)-5- (O-H …O)
2.413 Compound 35 (N-H …N) 2.710
(6-amino ASP 392:O H3C NH N
octahydro-9H- 6
ASN 395:N
44.40 9-benzyl- N - N
purin-9-yl)-3,4- N
(N-H ...O) methyl-(2-phenyl (O-H ...N)
dihydroxytetrahy N
2.721 50.26
2.516 ethyl)- adenine TYR 233:O
drofuran-2-yl] ASN395:N
ethyl}phosphonic
acid C21H21N5 (N-H ...O)
(N-H ...O) 2.502
2.506 TYR 233:O
C11H24N5O6P ASN 395:N
4. H 3C H with Protein Data Bank identifier 1TB5) using the docking programs
Compound 21 N
N
GOLD and GLIDE. Most of the ligand compounds that were docked
N
N6-methyl-9- (3,3- seemed to have interaction with the active site residues like ASN 395,
N
diphenyl propyl)-
N (N-H …N) TYR 233, ASP 392, HIS 234 and GLN 443. Other than this, residue ILE
2.467 51.12
adenine ILE 410:N 410 also exhibited interaction.
C21H21N5 PDB complex or co-crystal AMP in docking analysis was found to have a
gold sore of 44.40 and a glide score of -7.217 and the glide energy was
Compound 26 (N-H ...N) 2.452 found to be -52.002. From Ligplot of interactions with ligand (Pdb
ASN 395:N complex) and from Gold and Glide docking analysis of AMP, the active
9-benzyl-2-
site residues were found to be ASP 392, ASN 395, HIS 234, TYR 233,
cyclohexyl- N6- (N-H ...N)
methyladenine 2.401 52.25 GLU 304, THR 345, ASP 275,GLN 443, MET 347 & ILE 410.
GLN 443:N
C19H23N5 Among the compounds that were docked, compound 26 (9-benzyl-2-
(O-H...N) 2.709
TYR 233:O cyclohexyl-N6-methyladenine) has given the highest score compared to
other compounds (including co-crystallized ligand) in both GLIDE and
GOLD docking analysis. The compound 26 obtained the highest score of
Table 5: Induced Fit Docking Results
52.25 in GOLD and also it exhibited the best GLIDE docking score of -
Compounds Glide Glide Energy Hydrogen bond Distance 7.833 and glide energy of -45.723 and showed strong interactions with
Score (Kcal/Mol) Interactions between the residues ASN 395,GLN 443,ASP 392 and HIS 234 in the active site,
DH…A Donor and having hydrogen bonds of length 2.939, 2.855, 2.710 and 3.266 Å
Acceptor respectively.
(Å)
Cocrystal -7.217 -52.002 (NH…O) ASN 395 3.113 Other than compound 26, compounds 24 (9-benzyl-N6-methyl-2-n
Ligand AMP (OH…O) ASP 392 2.639 propyladenine), 38 (9-(2-methoxybenzyl)-N 6 -methyl-2-n-
6
HIS 234(NH…O) 2.811 propyladenine) and 42 (2-iodo-9- (2-methoxybenzyl)-N -
TYR 233(OH...O) 2.921 methyladenine) also exhibit good interactions with the receptor. Their
(OH…O)GLU 304 2.758 scores were better than the PDB complex AMP, which we have seen
Compound 21 -5.835 -47.244 HIS 278(NH…N) 3.101 above, exhibited a gold sore of 44.40 and a glide score of -7.216.
HIS 234(NH…N) 2.898 Compound 24 obtained a glide score of -7.521(Gold score 46.13) and has
(NH…O) ASP 275) 3.199 show strong interactions with active site residues ASN 395, TYR 233 &
GLN443 with hydrogen bonds of length 2.849,3.101 & 3.007 Å
Compound 11 -7.394 -39.044 (NH…O) ASN 395 2.905
respectively.
GLN 443(NH…N) 3.073
(NH…O)GLU 304 2.597 6
Compound 38 (9-(2-methoxybenzyl)-N -methyl-2-n-propyladenine)
HIS 278(NH…N) 3.001
was observed to have a glide score of -7.467(Gold score 47.47)
Compound 38 -7.659 -44.258 (NH…O) ASN 395 2.870 comparatively better than AMP scores and has shown strong interactions
GLN 443(NH…N) 3.134 with residues ASN 395,GLN443 & TYR 233 with hydrogen bonds of
(NH…O)GLN 443) 3.132 length 2.913, 3.134 & 2.625 Å respectively.
Compound 24 -7.521 -43.049 (NH…O) ASN 395 2.849
GLN 443(NH…N) 3.007 Surprisingly Compound 42(Raboisson et al., 2002), an iodo derivative
(NH…O) TYR 233 3.101 exhibited a glide score -7.394 and has shown strong interactions with
ASN 395(NH…N) 2.967 residues ASN 395,GLN 443, TYR 233, ASP 392 & HIS 234 with
hydrogen bonds of length 2.873, 3.018, 3.113, 2.791 & 3.153 Å
Compound 26 -7.833 -45.723 (NH…O) ASN 395 2.939
GLN 443(NH…N) 2.855 respectively.
ASN 395(NH…N) 2.869
Thus from studying the interactions which the above mentioned
(NH…O) ASP 392 2.710
compounds exhibited and comparing their Gold and Glide scores with
HIS 234(NH…N) 3.266
that of PDB complex AMP, we conclude that those ligands i.e.
Compound 26 -7.394 -42.439 (NH…O) ASN 395 2.873 compounds 26,24,38 & 42 have better interactions with the active site of
GLN 443(NH…N) 3.018 the target protein PDE4 and may possess potential PDE4 inhibitory
TYR 233(OH…N) 3.113
activity.
(NH…O) ASP 392 2.791
HIS 234(NH…N) 3.088 The type of interaction, which the inhibitors exhibit, and the active site
[Various poses (<20) were obtained by docking co-crystal AMP & other residues with which they interact convey that they are good inhibitors of
ligand compounds and the collective interactions (of several poses) with PDE4 as they exhibit drug like activity. The results suggest that the
active site residues for each ligand were shown in table] compounds (9-substituted adenine derivatives) herewith proposed are
more than one molecule E.g. a protein and a cofactor (Here its PDE4B showing orientation close to active site and the compounds 26,24,38 &
and AMP). GLIDE can be run in rigid or flexible docking modes; the 42 may be used as a lead for designing future pharmaceuticals that may
later automatically generates conformation for each input ligand. be used as potential inhibitors of PDE4.
Discussion References
In the present study, we proposed and evaluated the interaction of 9- 1) Clayton RA, Dick CAJ, Mackenzie A, Nagasawa M, Galbraith D,
substituted adenine derivatives with PDE4-isoform B (Target protein Hastings SF and MacKenzie SJ (2004), The effect of selective
5. phosphodiesterase inhibitors, alone and in combination, on a murine 6) Schmitz T, Souil E, Herve R, Nicco C, Batteux F, Germain G,
model of allergic asthma, Respiratory Research, 5(1):4. Dominique C, Brion DE, Leroy MJ and Mehats C (2007), PDE4
inhibition prevents Preterm delivery induced by an intrauterine
2) Dastidar SG, Ray A, Shirumalla R, Rajagopal D, Chaudry S, Nanda inflammation, The Journal of Immunology, 178: 1115-1121.
K, Sharma P, Seth MK, Balachandran S, Gupta N and Palle V (2009),
Pharmacology of a Novel, Orally Active PDE4 Inhibitor, 7) Schudt C, Tenor H and Hatzelmann A (1995), PDE isoenzymes as
Pharmacology,83:275-286. targets for anti-asthma drugs, Eur Respir J, 8:1179-1183..
3) Huai Q, Sun Y, Wang H, Macdonald D, Aspiotis R, Robinson H, 8) Smith VB, Spina D, and Page CP (2006), Phosphodiesterase
Huang Z and Ke H (2006), Enantiomer discrimination illustrated by Inhibitors, British Journal of Pharmacology, 147: S252-S2575
high resolution crystal structures of type 4 phosphodiesterase, J Med
Chem., 49(6): 1867-1873. 9. Warren GL, Andrews CW, Capelli AM, Clarke B, Lalonde J,
Lambert MH, Lindvall M, Nevins N, Semus SF, Senger S, Tedesco
4) Omori K and Kotera J (2007), Overview of PDEs and their G, Wall ID, Woolven JM, Peishoff CE and Head MS (2006), A
regulation, Circ. Res., 100:309-327. critical assessment of docking programs and scoring functions, J
Med Chem, 49(20): 912-931.
5) Raboisson P, Lugnier C, Muller C, Reimund JM, Schultz D, Pinna G,
Bec AL, Basaran H, Desaubry L, Gaudiot F, Seloum M and
1,3 Department of Biochemistry, Biotechnology and
Bourguignon JJ (2003), Design, Synthesis and structure-activity
Bioinformatics, Avinashilingam University for women,
relationships of a series of 9-substituted adenine derivatives as
Coimbatore
selective phosphodiesterase type-4 inhibitors, European journal of
2 Center of Advanced Study in Crystallography and Biophysics,
medicinal chemistry,38:199-214
University of Madras, Guindy campus, Chennai
For Correspondence : janagi.thirumurthy@rediffmail.com