MSIPPoster_NojanSheybani
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This study explored designing small molecule inhibitors of the NRMT1 enzyme. NRMT1 is an important methyltransferase enzyme that transfers methyl groups from SAM to its substrate RCC1. The deregulation of NRMT1 has been observed in cancers. Using molecular modeling programs Sybyl and GOLD, 14 small molecules were designed that were predicted to bind in the RCC1 binding site of NRMT1 and suppress its activity. The molecules were docked and scored using GOLD, and the top scoring molecules will be further optimized to improve their inhibitory activity against NRMT1.
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This document discusses peptidomimetics, which are small protein-like chains designed to mimic peptides while having no peptide bonds and a molecular weight under 700 Daltons. Peptidomimetics are derived from bioactive peptides and aim to improve stability, transport properties, and activity while reducing degradation. They are classified based on their modifications from the original peptide. Common modification methods include cyclization, retro-inverso design, and restricting conformations through disulfide bonds or metal chelation. Peptidomimetics have therapeutic value as they can overcome issues like poor oral bioavailability that limit peptide drugs, as demonstrated for somatostatin analogs. Recent advances include using peptidomimetics to enhance peptide vaccines
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3) Structure of enzymes - Shape, active & allosteric sites
4) Mechanism of action of enzymes- Substrate binding, catalysis, dynamics, allosteric modulation
5) Role of enzymes
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D) Adverse drug reactions due to enzyme inhibition
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B) JAK-STAT pathway
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A protein molecule
Present either in plasma membrane or cytoplasm
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It may be peptide, neurotransmitter, hormone, drug or toxins
Ligand may be agonist or antagonists
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Nevertheless, for the majority of GPCRs, the identity of their natural ligands is still unknown, hence remain orphan receptors.
The simple dogma that underpins much of our current understanding of GPCRs, namely,
one GPCR gene− one GPCR protein− one functional GPCR− one G protein −one response
is showing distinct signs of wear.
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This document discusses G-protein coupled receptors (GPCRs):
- GPCRs are the largest family of transmembrane receptors and play important roles in human senses and physiology. They respond to a wide range of ligands.
- GPCRs are classified into families based on sequence homology and functional similarity. The largest family is rhodopsin-like receptors which have 7 transmembrane domains.
- GPCRs are activated via conformational changes in the transmembrane domains, primarily involving movements of "microswitches" that allow the receptor to activate associated G proteins and downstream signaling.
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This document discusses ligand-receptor interactions, using estrogen receptor and estrogen as an example. It describes how ligands bind to specific receptors on target cells, inducing a conformational change and cellular response. It then details the domains of estrogen receptors, how estrogen binds and activates the receptors, and the role of the receptor domains in transcription. The discussion includes examples of covalent and non-covalent ligand-receptor interactions.
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1) Bacteria have sophisticated mechanisms to regulate biosynthesis of enzymes based on environmental conditions.
2) Enzyme production is induced when needed in the presence of substrates, and repressed when end products accumulate or alternative substrates are available.
3) Key regulatory mechanisms include feedback inhibition, enzyme induction, enzyme repression, and catabolite repression which prioritizes utilization of preferred carbon sources like glucose over others.
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This document provides information about a receptor pharmacology course taught by Professor Dr. Md. Shah Amran at the University of Dhaka. It was prepared by 5 students and contains an introduction to receptors, classifications of different receptor types including ligand gated ion channels, G-protein coupled receptors, enzyme linked receptors, and nuclear receptors. It also discusses receptor-drug interactions, affinity, intrinsic activity, and mechanisms of cell surface and intracellular receptors.
Abhishek Mogili USRTP Poster
1) The protein SAMP1 localizes to both the endoplasmic reticulum (ER) and microtubules, suggesting it may associate the ER with microtubules.
2) RNAi treatments to stop SAMP1 synthesis in HeLa cells resulted in changes to cell morphology, including the presence of stress fibers and abnormal mitotic cell shapes.
3) This indicates SAMP1 likely plays a role in cell adhesion and cytoplasmic structure.
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Non-receptor tyrosine kinases (nRTKs) are cytoplasmic enzymes that catalyze the transfer of phosphate groups from ATP to tyrosine residues in proteins. Unlike receptor tyrosine kinases, nRTKs lack extracellular and transmembrane domains. nRTKs contain two domains - a catalytic domain consisting of two lobes that facilitate ATP transfer, and a protein-protein interaction domain containing SH2 and SH3 subdomains. There are several families of nRTKs including Src, Abl, Syk, Jak, and Zap70 that perform critical functions in immune cell signaling through T cell and B cell receptors. Inhibitors of overactive nRTKs show promise for cancer treatment by blocking intracellular tumor processes.
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3. Experiments show the complex is a non-competitive inhibitor of LDH. It significantly reduces LDH activity in purified LDH, mice liver extract, and perfused mice liver.
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Alternative splicing is a process by which cells produce multiple protein isoforms from individual genes. Understanding the functions and interactions of alternatively spliced protein isoforms is important for understanding disease. A new study found that two proteins, PRMT1 and RBM15, regulate the differentiation of megakaryocytes, blood cells involved in platelet production, through alternative splicing. Mutations in these proteins have been linked to blood cancers. Further research on alternative splicing may help identify new disease targets and therapies.
POSTER FINAL
Prion-like domains are low-complexity sequences found in about 1% of human proteins that are similar to yeast prion domains and confer prion-like properties. Two algorithms, PAPA and PrionScan, were developed to predict prion-like domains based on different criteria, amino acid composition and sequence from yeast proteins respectively. TAF15 is an RNA-binding protein that contains a prion-like domain and has been implicated in cancers and amyotrophic lateral sclerosis through gene fusions and mutations that alter its functions in transcription, splicing, and stress response. HNRPDL is also predicted to have a prion-like domain based on the PAPA algorithm and shares similar features to
In silico drug discovery 2
This document summarizes a presentation on discovering inhibitors for the histone-lysine N-methyltransferase SETD2 using an in silico approach. It discusses methyltransferases and histone methyltransferases as a potential target. The hypothesis is that selective, high-affinity SETD2 inhibitors can be identified by targeting its SAM binding site. The methodology involves generating pharmacophore models using software and screening databases of compounds. Results show two pharmacophore models and top-hit compounds identified. The conclusions are that the SETD2 binding site is a potential drug target and compounds with high predicted binding energies were identified. Future work involves refining models and testing top compounds in assays.
Pharmacogenomics
The document discusses pharmacogenomics and how genetic variations can affect individual responses to drugs. It describes how pharmacogenomics examines genomic loci and biological pathways to determine drug variability. It also discusses pharmacogenetics which focuses on single gene variants. The document outlines some merits of pharmacogenomics like improving drug safety and personalized treatment. It then discusses various scenarios on how genetic polymorphisms can impact different drug metabolism pathways. Finally, it examines how specific genetic variations in drug metabolizing enzymes and transporters can influence drug pharmacokinetics and potential adverse effects.
NMT_JMedChem1
This document summarizes research on the discovery of a novel class of orally active inhibitors of N-myristoyltransferase (NMT) that are trypanocidal, meaning they can kill the parasite Trypanosoma brucei which causes Human African Trypanosomiasis (HAT). Researchers screened over 63,000 compounds and identified a hit compound (1) that inhibited T. brucei NMT with low micromolar potency and also had activity against the parasite. They then optimized the hit through structure-activity relationship studies, improving potency against the enzyme and parasite as well as developing good oral pharmacokinetics. This led to a lead compound, DDD85646 (
SF and PE CTR-IN 2016 Poster_FInal
This document describes computational techniques used to design novel competitive inhibitors of the E. coli 5'-methylthioadenosine/S-adenosylhomocysteine nucleosidase (MTN) enzyme. It utilized core hopping to generate 10,000 structures by varying the core while keeping functional groups constant. Docking and binding energies were calculated for subsets of compounds down to the top 8 ligands. Results show several compounds have more favorable predicted binding than the control TDI inhibitor, warranting further optimization and testing of lead compounds.
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- The document examines the role of plasminogen activator inhibitor 1 (PAI-1) in the recruitment of mast cells (MCs) to glioma tumors.
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- Activation of the potential PAI-1/LRP1 axis in MCs by purified PAI-1 promotes increased phosphorylation of STAT3 and subsequent MC exocytosis. This indicates the PAI-1/LRP1 axis influences MC recruitment in glioma tumors.
Rna editing as a drug target identification of inhibitors of rel 1 bsp 2010
(1) RNA editing is essential in trypanosomatids and is catalyzed by editosomes containing the essential enzyme REL1, which has no close human homologs and is thus a potential drug target.
(2) Molecular dynamics simulations were used to virtually screen compounds, identifying three initial inhibitors of REL1 with low micromolar IC50 values.
(3) Additional screening of databases identified 588 related compounds, of which 25 top candidates inhibited REL1 in biochemical assays with IC50 values of 1-10 μM. Efforts are underway to improve activity and selectivity.
Control of gene expression
Definition, Principle, gene expression in eukaryotes, levels of gene control, genes and regulatory elements, Operon system
Applications of protein array in diagnostics and genomic and proteomic
icroarray technology can simultaneously analyze thousands of parameters in a single experiment. Micro-point of capture molecules are fixed into ranks on a solid support and exposed to samples containing corresponding binding molecules. Complex formation in each micro-point can be detected by the readout system, which is based on fluorescence, chemiluminescence, mass spectrometry, radioactive or electrochemistry. Miniaturization and parallelization binding assays, whose analysis power can be also enlarged by microarray gene expression analysis, is sensitive. These systems can be used to detect the degree of hybridization and immobilized DNA microarray probes will be exposed to complementary target. Currently, the development of protein array has demonstrated its applications in enzyme-substrate, DNA- protein and different types of protein - protein interactions. In this post, we will discuss the capture-molecule-ligand analysis, analyze its theoretical advantages and disadvantage and its influence in diagnostics, genomic and proteomics.
Applications of protein array in diagnostics and genomic and proteomic
Microarray technology can simultaneously analyze thousands of parameters in a single experiment. Micro-point of capture molecules are fixed into ranks on a solid support and exposed to samples containing corresponding binding molecules. Complex formation in each micro-point can be detected by the readout system, which is based on fluorescence, chemiluminescence, mass spectrometry, radioactive or electrochemistry. Miniaturization and parallelization binding assays, whose analysis power can be also enlarged by microarray gene expression analysis, is sensitive. These systems can be used to detect the degree of hybridization and immobilized DNA microarray probes will be exposed to complementary target. Currently, the development of protein array has demonstrated its applications in enzyme-substrate, DNA- protein and different types of protein - protein interactions. In this post, we will discuss the capture-molecule-ligand analysis, analyze its theoretical advantages and disadvantage and its influence in diagnostics, genomic and proteomics.
In silico discovery of histone methyltranferase 1
This study investigated potential inhibitors of the histone methyltransferase SETD2 using in silico methods. Two pharmacophore models were generated and used to screen a database of 150,000 compounds, filtering it to 31,669 potential leads. Molecular docking ranked these by predicted binding energy, identifying 58 compounds with binding energies from -9.7 to -9.0 kcal/mol. Further refinement of the models and testing of top-scoring compounds may reveal inhibitors of histone methylation and cancer progression.
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Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1)
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Rna editing as a drug target identification of inhibitors of rel 1 bsp 210
Rna editing as a drug target identification of inhibitors of rel 1 bsp 210
Eukaryotic RNA processing: alternative RNA splicing
Eukaryotic RNA processing: alternative RNA splicing
Rna editing as a drug target identification of inhibitors of rel 1 bsp 2010
Rna editing as a drug target identification of inhibitors of rel 1 bsp 2010
Applications of protein array in diagnostics and genomic and proteomic
Applications of protein array in diagnostics and genomic and proteomic
Applications of protein array in diagnostics and genomic and proteomic
Applications of protein array in diagnostics and genomic and proteomic
MSIPPoster_NojanSheybani
- 1. Designing Small Molecules as potential inhibitors of NRMT1 Enzyme Nojan Sheybani, Yunfei Mao, Dr. Rong Huang Department of Medicinal Chemistry, Institute for Structural Biology and Drug Discovery Virginia Commonwealth University 800 E Leigh St., Suite 212, Richmond, VA 23219 Email: nickshey@gmail.com •NRMT plays an essential role in the cell cycle as knockdown of its function results in mitotic defects. •NRMT-catalyzed reaction involves a protein substrate and the S-adenosylmethionine (SAM) cofactor. A fluorescence-based assay is adopted to evaluate the activities of bisubstrate analogs and determine the inhibitory mechanism using recombinant NRMT. ● Small molecules that could potentially inhibit the activity of the NRMT1 enzyme were designed. ● Sybyl and GOLD were used to study how the small molecules would bind into the RCC1 binding sight. ● Further optimization of the small molecules are required to improve the inhibiting activity. Abstract NRMT1 is an important enzyme which plays an important role in a post-translational process called methylation and it transfers a methyl group from a molecule called S-Adenosyl methionine (SAM) to its substrate, RCC1. There are two different binding sites found in this specific enzyme: S-Adenosyl methionine (SAM) and the chromosomal protein, RCC1. Throughout time, there have been many different molecules that have been docked to try and inhibit the N-terminal methyltransferase enzyme, NRMT1, the only human protein. The deregulation of NRMT1 was observed in different cancers and also plays an important role in regulating protein DNA-binding; so, to study the function of this enzyme, different small molecules were designed. There are three types of small molecule inhibitors: inhibitors which inhibit the binding of SAM, those which inhibit the binding of RCC1, and, finally, those which are bisubstrate inhibitors, inhibiting both SAM and RCC1. In this study, we mainly focused on the small molecules that would inhibit the RCC1 binding site. The purpose of this experiment was to develop potential inhibitors from the molecules that were modeled for this enzyme. We are hoping that these inhibitors could potentially act as chemical probes in the analysis of NRMT function in numerous systems. In order to inhibit this enzyme, there would have to be molecules that would fill in the pockets and inhibit them from being activated and, furthermore, neutralizing it. Many molecules were tested to see if they had the potential to inhibit the enzyme. In this study, we explored the effect that different molecules would have on an NRMT1 enzyme catalyzing the methylation of RCC1. Using two molecular modeling programs, Sybyl and GOLD, we were able to model 14 different molecules that were thought to have a good chance of suppressing the activity of the enzyme. Then through docking using GOLD, we obtained the scores for each molecule, then by looking at the way molecules bind into the pocket, we are going to further optimize the structure in order to enhance the inhibiting activity of the inhibitors. Introduction Research Plan Acknowledgements Conclusions Data This picture represents the intermediate states of SAH and RCC1 binding with NRMT1. Special thanks to Yunfei Mao, Dr. Rong Huang, and the rest of the Huang lab members from the department of Medicinal Chemistry at Virginia Commonwealth University. 9 4 3 These molecules were some of many to be docked onto the NRMT1 enzyme to test their inhibitory effects. Gold Score Results Small Molecule and Solution Chemical Score YM5 Solution 4 28.2142 YM13 Solution 3 26.8118 YM9 Solution 5 25.9702 YM3 Solution 10 25.7579 YM4 Solution 9 25.7458 YM5 Solution 6 25.6972 YM14 Solution 5 24.7959 YM11 Solution 5 22.5731 YM6 Solution 1 21.8363 YM2 Solution 8 15.3365