Global ETD Search

21	Sensitivity Enhancement of Liquid-State NMR and Improvement of the INPHARMA Method / Empfindlichkeitssteigerung der Flüssigkeits-NMR und Verbesserung der INPHARMA Methode Reese, Marcel 08 April 2010 (has links) No description available. 000 Allgemeines Wissenschaft Physics 35.25
22	Conception, synthèse et dévelopement d'inhibiteurs du répresseur transcriptionnel mycobactérien ETHR selon une approche par fragments. Une nouvelle approche dans la lutte contre la tuberculose / Use of fragment-based approaches for the design, synthesis and development of new ethr inhibitors as a new strategy to fight tuberculosis Villemagne, Baptiste 28 September 2012 (has links) Avec plus d’un million et demi de morts chaque année, la tuberculose reste aujourd’hui la seconde cause de mortalité liée à un agent infectieux. De plus l’organisation mondiale de la santé (OMS) a estimé en 2011 qu’un tiers de la population mondiale était porteuse du bacille Mycobacterium tuberculosis responsable de la maladie. Depuis la fin des années 1980, une recrudescence du nombre de cas de tuberculose est observée à l’échelle mondiale. Cette recrudescence est due à la fois à l’apparition de souches résistantes, mais également à l’épidémie de VIH qui est un facteur de prédisposition au déclenchement de la maladie.En 2000, le répresseur transcriptionnel mycobactérien EthR a été identifié comme étant un régulateur clé dans la bioactivation de l’éthionamide (ETH), un antituberculeux utilisé pour le traitement de seconde intention. En 2009, l’inhibition de ce répresseur par le développement de molécules « drug-like » a permis de potentialiser l’activité de l’éthionamide d’un facteur 3 chez la souris infectée et a permis de valider cette cible pour une future approche thérapeutique.Ce travail repose sur la découverte et l’optimisation de nouveaux inhibiteurs de ce répresseur transcriptionnel mycobactérien, à partir d’une petite molécule appelée « fragment » qui a été cocristallisée avec la protéine. Par la combinaison d’un criblage in silico, d’un criblage in vitro des touches identifiées, de l’étude des structures radiocristallographiques des complexes ligands/protéines et de la chimie médicinale, le développement de trois approches complémentaires dites « fragmentgrowing », « fragment-merging » et « fragment-linking » a permis de développer des composés présentant de fortes activités. Ces résultats permettront très prochainement de sélectionner une nouvelle molécule issue de ce travail dans la perspective de nouveaux essais sur le modèle murin. / Tuberculosis (TB) remains the leading cause of death due to a single infective agent with more than 1.5 million people killed each year. In 2011, the world health organization (WHO) estimated that one third of the world’s population is infected with Mycobacterium tuberculosis, the pathogen responsible for the disease. This phenomenon may be due to an explosive escalation of TB incidence that occurred in the 1980s due to the emergence of both resistant strains and HIV epidemic.In 2000, EthR, a mycobacterial transcriptional repressor, was identified as a key modulator of ethionamide (ETH) bioactivation. ETH is one of the main second-line drugs used to treat drug resistant strains. In 2009, it was shown that co-administration of ETH and drug-like inhibitors of EthR was able to boost ETH activity threefold in a mouse-model of TB-infection, thus validating the target for a new therapeutic strategy.This work deals with the discovery and optimisation of new EthR inhibitors, based on a small molecule, called a “fragment”, co-crystallized with the protein. We combined in silico screening, in vitro evaluation of the hit compounds, study of co-crystal structures and medicinal chemistry to develop three complementary approaches called “fragment growing”, “fragment merging” and “fragment linking” that led to the discovery of very potent inhibitors. Based on these results, we are currently selecting a potential candidate for new in vivo experiments. Inhibiteur d'EthR Criblage in silico Approche par fragments Tuberculose Mycobacterium tuberculosis Éthionamide Potentialisation Répresseur transcriptionnel Conception rationnelle FBDD Tuberculosis Mycobacterium tuberculosis, EthR Ethionamide Boosting strategy Transcriptional repressor, Fragment-based approaches In silico screening, Structure-based drug design
23	Triagem virtual de inibidores da enzima di-hidrofolato redutase de Schistosoma mansoni (SmDHFR) / Virtual screening of dihydrofolate reductase Schistosoma mansoni (SmDHFR) enzyme inhibitors. João Paulo Machado Martins 17 August 2017 (has links) A esquistossomose é uma das principais causas de morbidade em países Tropicais e Subtropicais, gerando graves consequências socioeconômicas. Atualmente, os fármacos disponíveis para o tratamento da desta doença são praziquantel e oxamniquina, porém relatos de baixa susceptibilidade do parasita a esses medicamentos sugerem a necessidade de novas estratégias terapêuticas para o tratamento da doença. Todavia, existe pouco interesse da indústria farmacêutica no desenvolvimento de fármacos contra doenças tropicais e negligenciadas, entre as quais se encontra a esquistossomose. Devido a estes fatores, o presente trabalho teve por objetivo geral utilizar ferramentas computacionais para identificar inibidores da SmDHFR candidatos a novos fármacos. Avaliou-se as características exclusivas para a proteína de S. mansoni por meio de uma análise das sequências FASTA em comparação com a DHFR de outros organismos. A fim de garantir a ação seletiva dessas moléculas frente a enzima do parasita, os campos moleculares de interação seletivos para SmDHFR foram calculados e empregados na construção do modelo farmacofórico, o qual foi utilizado na triagem virtual de inibidores de SmDHFR. Os estudos computacionais realizados nos permitiram a seleção de 20 moléculas com uma boa complementariedade com o modelo farmacofórico gerado e com potencial para serem inibidores de SmDHFR. / Schistosomiasis is one of morbidity\'s main causes in tropical and subtropical countries, which leads to serious socioeconomic consequences. Praziquantel and oxamniquina are the drugs currently available for treating this disease, but reports points that the parasite has been resistant to both drugs, which suggests the need for new therapeutic strategies for the treatment of this disease. However, there is little interest in the pharmaceutical industry in developing drugs against neglected tropical diseases, including schistosomiasis. Due to these factors, the present work has the general objective to use computational tools to identify SmDHFR inhibitors which could be good candidates for developing new drugs. Evaluation of the exclusive characteristics of the S. mansoni protein were performed by FASTA sequence analyses in comparison to DHFR from other organisms. In order to guarantee the selective action of these molecules against the parasite enzyme, the molecular interaction fields selective for SmDHFR were calculated and used in the construction of the pharmacophoric model, which was further used in the virtual screening of SmDHFR inhibitors. Computational studies were performed and those led us to 20 molecules with a good complementarity with the pharmacophoric model that was previously generated and with potential to be SmDHFR inhibitors. Acoplamento Molecular Di-hidrofolato Redutase GRID/PCA Schistosoma mansoni Dihydrofolate Reductase GRID / PCA Molecular coupling Schistosoma mansoni Structure Based Drug Design (SBDD)
24	Cellular and Computational Evaluation of the Structural Pharmacology of Delta Opioid Receptors Yazan J Meqbil (14210360) 05 December 2022 (has links) <p>G-protein coupled receptors (GPCRs) are membrane proteins that constitute ~30% of the FDA-approved drug targets. Opioid receptors are a subtype of GPCRs with four different receptor types: delta, kappa, mu, and nociception opioid receptors. Opioids such as morphine have been used for thousands of years and are deemed the most effective method for treating pain. However, opioids can have detrimental effects if used illicitly or over an extended period of time. Intriguingly, most of the clinically used opioids act on the mu opioid receptor (µOR). Hence, efforts in recent decades have focused on other opioid receptors to treat pain and other disorders. The delta opioid receptor (δOR) is one of four opioid receptors expressed in the central and peripheral nervous system. The δOR has attracted much attention as a potential target for a multitude of diseases and disorders including substance and alcohol use disorders, ischemia, migraine, and neurodegenerative diseases. However, to date, no δOR agonists, or drugs that act directly at the δOR, have been successful as clinical candidates. Nonetheless, the therapeutic potential of the δOR necessitates the targeting its pharmacologically. In this dissertation, I highlight peptide-based modulation as well as the identification of novel agonists at the δOR. I report research findings in the context of biased agonism at δOR, which is a hypothesized cellular signaling mechanism with potential therapeutic benefits. The focus on this work is the molecular determinants of biased agonism, which were investigated using a combination of cellular and computational approaches. </p> Basic pharmacology Biomolecular modelling and design Proteins and peptides Computational chemistry structure-based drug design (SBDD) Opioid Receptors Signaling Hit identification Molecular modeling
25	Structure-Based Computer Aided Drug Design and Analysis for Different Disease Targets Kumari, Vandana 13 September 2011 (has links) No description available. Bioinformatics Biophysics Pharmacy Sciences structure-based drug design Molecular modeling protein structure prediction virtual screening Free energy calculation molecular dynamic simulation Molecular docking Surface plasmon resonance
26	Theoretical Studies of Molecular Recognition in Protein-Ligand and Protein-Protein Complexes Yang, Hui January 2010 (has links) No description available. Chemistry quantum chemical molecular recognition supermolecular approach solvation correction nonbonded interactions HIV-1 Reverse Transcriptase non-nucleoside inhibitor trp 229 Botulinum neurotoxin B synaptotagmin II ASADH structure-based drug design
27	Structural Investigation of Processing α-Glucosidase I from Saccharomyces cerevisiae Barker, Megan 20 August 2012 (has links) N-glycosylation is the most common eukaryotic post-translational modification, impacting on protein stability, folding, and protein-protein interactions. More broadly, N-glycans play biological roles in reaction kinetics modulation, intracellular protein trafficking, and cell-cell communications. The machinery responsible for the initial stages of N-glycan assembly and processing is found on the membrane of the endoplasmic reticulum. Following N-glycan transfer to a nascent glycoprotein, the enzyme Processing α-Glucosidase I (GluI) catalyzes the selective removal of the terminal glucose residue. GluI is a highly substrate-specific enzyme, requiring a minimum glucotriose for catalysis; this glycan is uniquely found in biology in this pathway. The structural basis of the high substrate selectivity and the details of the mechanism of hydrolysis of this reaction have not been characterized. Understanding the structural foundation of this unique relationship forms the major aim of this work. To approach this goal, the S. cerevisiae homolog soluble protein, Cwht1p, was investigated. Cwht1p was expressed and purified in the methyltrophic yeast P. pastoris, improving protein yield to be sufficient for crystallization screens. From Cwht1p crystals, the structure was solved using mercury SAD phasing at a resolution of 2 Å, and two catalytic residues were proposed based upon structural similarity with characterized enzymes. Subsequently, computational methods using a glucotriose ligand were applied to predict the mode of substrate binding. From these results, a proposed model of substrate binding has been formulated, which may be conserved in eukaryotic GluI homologs. Biomolecular structure Eukaryotic glycosylation glycosylation N-glycan N-linked glycosylation Carbohydrate biochemistry Inhibitor antiviral therapeutic Structure-based drug design glucosidase glycosidase glycoside hydrolase post-translational modification enzyme enzyme mechanism inverting mechanism structural biology protein structure 6xHis tag Crystal packing sugar substrate X-ray crystallography single anomalous dispersion PHENIX heavy-atom phasing docking autodock autodock vina biophysical methods tryptophan fluorescence glucose oxidase activity assay enzyme inhibition Protein expression Protein purification Pichia pastoris Saccharomyces cerevisiae fondue AOX1 promoter glycoside hydrolysis substrate binding model molecular dynamics molecular dynamics Binding site Active site cleft Endoplasmic reticulum Glycan processing Glycan trimming protein-protein interactions cell-cell communication X-ray diffraction crystallization secreted protein substrate selectivity kojibiose glucotriose miglitol deoxynojirimycin Glc3Man9GlcNAc2 free oligosaccharide species GluI Cwh41 Cwh41p Cwht1p 0306 0307 0760
28	Structural Investigation of Processing α-Glucosidase I from Saccharomyces cerevisiae Barker, Megan 20 August 2012 (has links) N-glycosylation is the most common eukaryotic post-translational modification, impacting on protein stability, folding, and protein-protein interactions. More broadly, N-glycans play biological roles in reaction kinetics modulation, intracellular protein trafficking, and cell-cell communications. The machinery responsible for the initial stages of N-glycan assembly and processing is found on the membrane of the endoplasmic reticulum. Following N-glycan transfer to a nascent glycoprotein, the enzyme Processing α-Glucosidase I (GluI) catalyzes the selective removal of the terminal glucose residue. GluI is a highly substrate-specific enzyme, requiring a minimum glucotriose for catalysis; this glycan is uniquely found in biology in this pathway. The structural basis of the high substrate selectivity and the details of the mechanism of hydrolysis of this reaction have not been characterized. Understanding the structural foundation of this unique relationship forms the major aim of this work. To approach this goal, the S. cerevisiae homolog soluble protein, Cwht1p, was investigated. Cwht1p was expressed and purified in the methyltrophic yeast P. pastoris, improving protein yield to be sufficient for crystallization screens. From Cwht1p crystals, the structure was solved using mercury SAD phasing at a resolution of 2 Å, and two catalytic residues were proposed based upon structural similarity with characterized enzymes. Subsequently, computational methods using a glucotriose ligand were applied to predict the mode of substrate binding. From these results, a proposed model of substrate binding has been formulated, which may be conserved in eukaryotic GluI homologs. Biomolecular structure Eukaryotic glycosylation glycosylation N-glycan N-linked glycosylation Carbohydrate biochemistry Inhibitor antiviral therapeutic Structure-based drug design glucosidase glycosidase glycoside hydrolase post-translational modification enzyme enzyme mechanism inverting mechanism structural biology protein structure 6xHis tag Crystal packing sugar substrate X-ray crystallography single anomalous dispersion PHENIX heavy-atom phasing docking autodock autodock vina biophysical methods tryptophan fluorescence glucose oxidase activity assay enzyme inhibition Protein expression Protein purification Pichia pastoris Saccharomyces cerevisiae fondue AOX1 promoter glycoside hydrolysis substrate binding model molecular dynamics molecular dynamics Binding site Active site cleft Endoplasmic reticulum Glycan processing Glycan trimming protein-protein interactions cell-cell communication X-ray diffraction crystallization secreted protein substrate selectivity kojibiose glucotriose miglitol deoxynojirimycin Glc3Man9GlcNAc2 free oligosaccharide species GluI Cwh41 Cwh41p Cwht1p 0306 0307 0760

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