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The Global ETD Search service is a free service for researchers
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Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
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Estudos de HQSAR, acoplamento molecular e cálculos de propriedades eletrônicas de compostos com atividade biológica frente aos alvos DPP-IV e FAPaMartins, Michelle Cristiane Melo Reis January 2018 (has links)
Orientadora: Profa. Dra. Káthia Maria Honório / Dissertação (mestrado) - Universidade Federal do ABC, Programa de Pós-Graduação em Ciência e Tecnologia/Química, Santo André, 2018. / Um dos alvos biologicos relacionado ao controle da glicemia e a enzima dipeptidil peptidase-IV (DPP-IV); ela esta associada com a estimulacao do pancreas na producao de insulina, sendo, portanto, um alvo de interesse da pesquisa e da industria farmaceutica para o tratamento do diabetes tipo 2. O diabetes e uma doenca cronica que se caracteriza por um aumento da glicemia causando uma serie de complicacoes fisiologicas com destaque para as doencas cardiacas como a aterosclerose; estima-se que 425 milhoes de pessoas sejam portadoras da doenca. Estudos indicam que inibidores da DPP-IV tambem podem apresentar acao sobre a FAP¿¿, uma enzima que esta relacionada com reparacao de tecidos e crescimento de tumores. Este trabalho consiste em utilizar metodos de modelagem molecular, como a construcao e analise de modelos de HQSAR (Hologram Quantitative Structure-Activity) e de CoMFA (analise comparativa de campos de interacao molecular); acoplamento molecular (docking), analise de propriedades eletronicas e deteccao e caracterizacao de sitios de ligacao da enzima FAP¿¿, com intuito de compreender as principais caracteristicas de ambas as enzimas, assim como a interacao das mesmas com uma serie de compostos bioativos. Os modelos CoMFA construidos apresentaram significativos valores de validacao interna (0,768) e externa (0,986); o alinhamento obtido utilizando a tecnica de acoplamento molecular e complementada com o uso da tecnica BINANA delineou as principais interacoes das enzimas com o conjunto de ligantes; identificou-se tres sitios de ligacao da enzima FAP¿¿ utilizando os servidores FTSite e FTMap. Desta forma, com informacoes sobre ambos os alvos e as interacoes estabelecidas com os ligantes, sera possivel propor com maior seguranca modificacoes moleculares para tais compostos candidatos a farmacos mais seguros para o tratamento do diabetes tipo 2. / One of the biological targets related to glycemic control is the dipeptidyl peptidase IV (DPP-IV) enzyme; it is associated with stimulation of the pancreas in insulin production and it is a target of interest for the researches related to the treatment of type 2 diabetes. Diabetes is a chronic disease characterized by an increase in blood glucose causing a series of physiological complications such as atherosclerosis, it is estimated that 425 million people have this disease. Studies have indicated that DPP-IV inhibitors may also have action on FAPá, an enzyme that is related to tissue repair and tumor growth. This work consists of using molecular modeling methods, such as the construction and analysis of HQSAR (Hologram Quantitative Structure-Activity) and CoMFA (comparative analysis of molecular interaction fields) models; molecular docking, analysis of electronic properties, detection and characterization of FAPá enzyme binding sites, and pharmacokinetic and pharmacodynamic properties studies; in order to understand the main characteristics of both enzymes, as well as their interaction with a series of bioactive compounds. The CoMFA models presented significant values of internal validation (0,768) and external (0,986) and the alignment obtained using the molecular docking technique outlined the main interactions of the enzymes with the set of ligands. With information on both targets and the interactions established with the ligands, it will be possible to more safely propose molecular modifications for such safer drug candidates for the treatment of type 2 diabetes.
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Caractérisation d’inhibiteurs d’anhydrase carbonique IX, études de complexes supramoléculaires et interactions moléculaires par résonance plasmonique de surface / Characterization of carbonic anhydrase IX inhibitors, studies of supramolecular complexes and molecular interactions by surface plasmon resonanceFlorent, Tiphaine 05 December 2014 (has links)
L’anhydrase carbonique IX (AC IX h) est une enzyme souvent associée à un mauvais pronostic, à la progression tumorale et à la régulation du pH extracellulaire des cellules tumorales sur un plan moléculaire. L’AC IX est très peu exprimée dans les tissus sains mais par contre, elle est surexprimée au sein de la masse tumorale, ce qui permet de la qualifier comme une cible thérapeutique potentielle. Une nouvelle classe d’inhibiteurs d’anhydrase carbonique IX a été conçue et synthétisée par notre équipe. Cette série de composés présente une solubilité aqueuse faible, limitant ainsi son développement pharmaceutique. La complexation de ces composés avec des cyclodextrines offre la possibilité d’améliorer leur solubilité et leur biodisponibilité sans affecter leur structure originale. Des études de complexation entre nos composés et diverses cyclodextrines ont été réalisées, afin de déterminer le complexe supramoléculaire le plus adéquat. Les études des complexes Analyte / Cyclodextrine ont été réalisées par deux techniques complémentaires, la résonance magnétique nucléaire et l’électrophorèse capillaire. La complexation de six sulfonamidodiarylpyrazoles originaux avec six cyclodextrines (-, - et - CDs, hydroxypropyle HP--CD, méthyle Me--CD ou amino NH2--CD) a été étudiée au pH physiologique. Les constantes de complexation, la stœchiométrie et l’étude structurale des complexes ont alors été déterminées. Par ailleurs, la présence d’un centre d’asymétrie dans la série des alcools secondaires, synthétisés sous leurs formes racémiques, a orienté nos travaux vers le développement de méthodes séparatives à l’échelle préparative afin de disposer de quantités suffisantes d’énantiomères permettant la détermination de leurs affinités pour la cible. Les séparations chirales ont été mises au point par chromatographie liquide haute performance, par chromatographie en phase supercritique ou par électrophorèse capillaire. La caractérisation de quatre analytes vis-à-vis de l’anhydrase carbonique II (AC II) a été réalisée, dans un premier temps, par des études d’interaction moléculaire utilisant des méthodes biophysiques qui ne nécessitent pas de marquage des partenaires, la résonance plasmonique de surface, la calorimétrie de titration isotherme et la thermal shift assay. L’objectif de cette comparaison était de valider les résultats obtenus mais aussi de sélectionner la méthode d’analyse permettant l’étude d’une grande série de composés avec l’isoforme d’intérêt (AC IX). Les résultats obtenus nous ont conduits à choisir la résonance plasmonique de surface (RPS) comme technique de choix pour l’étude de l’affinité des sulfonamidodiarylpyrazoles. Les affinités de seize composés pour trois isoformes (AC II, IX et XII) ont ensuite été déterminées par RPS. Des affinités de l’ordre du nanomolaire ont été obtenues pour les trois isoformes. De cette étude, deux composés possédant une affinité intéressante pour l’AC IX et une sélectivité AC IX versus AC II ont été selectionnés. De plus, l’étude de l’affinité des composés optiquement purs a permis de mettre en évidence une énantioselectivité isoforme dépendante. / Carbonic anhydrase (CA) IX expression is increased upon hypoxia and has been proposed as a therapeutic target since it has been associated with poor prognosis, tumor progression and pH regulation. A new class of human carbonic anhydrase IX (hCA IX) inhibitors, diarylpyrazole sulfonamide derivatives, has been synthesized in our team. These compounds have a very limited water solubility which limits their pharmaceutical development. The complexation with cyclodextrins (CDs) offers the possibility to improve their solubility without affecting their original structure and has proved to be one of the most effective. The studies of the complexes formed between our compounds and various CDs have been performed, in order to choose the most appropriate CD. We investigate by NMR and capillary electrophoresis the complexes formed between six original diarylpyrazole sulfonamide derivatives and six CDs (native -, - and - CDs, hydroxypropylated HP--CD, methylated Me--CD or amino NH2--CD) at physiological pH. Futhermore, as these compounds have a chiral center, it was essential to separate their enantiomers and verify their optical purities before envisaging the study of their pharmacological activity. The enantiomeric purification was performed by three separative methods, the high performance liquid chromatography, the supercritical fluid chromatography and the capillary electrophoresis. This study permit to obtain optically pure compound in order to determine affinity of carbonic anhydrase. To determine the affinities of derivatives with isoforms, we performed first a comparison of three label-free methods for quantitative assessment of binding strength between carbonic anhydrase II and sulfonamides derivatives. The formation constants have been determined by surface plasmon resonance, isothermal titration calorimetry and thermal shift assay, which characterize the interaction between two partners. This study was useful to select and to validate the surface plasmon resonance (SPR) for the molecular interaction between carbonic anhydrases and all our derivatives. Affinities of sixteen compounds for three carbonic anhydrase isoforms (CA II, IX and XII) were then determined by SPR. These compounds have nanomolar affinities for three isoforms. Two compounds have affinities with great interest for the isoform CA IX, and a good selectivity CA IX versus CA II and should be considered as lead compounds. Additionally, some of optically pure compounds have shown an enantioselectivity for the AC isoforms
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Development of high-performance algorithms for a new generation of versatile molecular descriptors. The Pentacle softwareDurán Alcaide, Ángel 04 March 2010 (has links)
The work of this thesis was focused on the development of high-performance algorithms for a new generation of molecular descriptors, with many advantages with respect to its predecessors, suitable for diverse applications in the field of drug design, as well as its implementation in commercial grade scientific software (Pentacle). As a first step, we developed a new algorithm (AMANDA) for discretizing molecular interaction fields which allows extracting from them the most interesting regions in an efficient way. This algorithm was incorporated into a new generation of alignmentindependent molecular descriptors, named GRIND-2. The computing speed and efficiency of the new algorithm allow the application of these descriptors in virtual screening. In addition, we developed a new alignment-independent encoding algorithm (CLACC) producing quantitative structure-activity relationship models which have better predictive ability and are easier to interpret than those obtained with other methods. / El trabajo que se presenta en esta tesis se ha centrado en el desarrollo de algoritmos de altas prestaciones para la obtención de una nueva generación de descriptores moleculares, con numerosas ventajas con respecto a sus predecesores, adecuados para diversas aplicaciones en el área del diseño de fármacos, y en su implementación en un programa científico de calidad comercial (Pentacle). Inicialmente se desarrolló un nuevo algoritmo de discretización de campos de interacción molecular (AMANDA) que permite extraer eficientemente las regiones de máximo interés. Este algoritmo fue incorporado en una nueva generación de descriptores moleculares independientes del alineamiento, denominados GRIND-2. La rapidez y eficiencia del nuevo algoritmo permitieron aplicar estos descriptores en cribados virtuales. Por último, se puso a punto un nuevo algoritmo de codificación independiente de alineamiento (CLACC) que permite obtener modelos cuantitativos de relación estructura-actividad con mejor capacidad predictiva y mucho más fáciles de interpretar que los obtenidos con otros métodos.
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Homology modeling and structural analysis of the antipsychotic drugs receptoromeLópez Muñoz, Laura 22 June 2010 (has links)
Classically it was assumed that the compounds with therapeutic effect exert their action interacting with a single receptor. Nowadays it is widely recognized that the pharmacological effect of most drugs is more complex and involves a set of receptors, some associated to their positive effects and some others to the side effects and toxicity. Antipsychotic drugs are an example of effective compounds characterized by a complex pharmacological profile binding to several receptors (mainly G protein-coupled-receptors, GPCR). In this work we will present a detailed study of known antipsychotic drugs and the receptors potentially involved in their binding profile, in order to understand the molecular mechanisms of the antipsychotic pharmacologic effects.The study started with obtaining homology models for all the receptors putatively involved in the antipsychotic drugs receptorome, suitable for building consistent drug-receptor complexes. These complexes were structurally analyzed and compared using multivariate statistical methods, which in turn allowed the identification of the relationship between the pharmacological properties of the antipsychotic drugs and the structural differences in the receptor targets. The results can be exploited for the design of safer and more effective antipsychotic drugs with an optimum binding profile. / Tradicionalmente se asumía que los fármacos terapéuticamente efectivos actuaban interaccionando con un único receptor. Actualmente está ampliamente reconocido que el efecto farmacológico de la mayoría de los fármacos es más complejo y abarca a un conjunto de receptores, algunos asociados a los efectos terapéuticos y otros a los secundarios y toxicidad. Los fármacos antipsicóticos son un ejemplo de compuestos eficaces que se caracterizan por unirse a varios receptores simultáneamente (principalmente a receptores unidos a proteína G, GPCR). El trabajo de la presente tesis se ha centrado en el estudio de los mecanismos moleculares que determinan el perfil de afinidad de unión por múltiples receptores de los fármacos antipsicóticos.En primer lugar se construyeron modelos de homología para todos los receptores potencialmente implicados en la actividad farmacológica de dichos fármacos, usando una metodología adecuada para construir complejos fármaco-receptor consistentes. La estructura de estos complejos fue analizada y se llevó a cabo una comparación mediante métodos estadísticos multivariantes, que permitió la identificación de asociaciones entre la actividad farmacológica de los fármacos antipsicóticos y diferencias estructurales de los receptores diana. Los resultados obtenidos tienen interés para ser explotados en el diseño de fármacos antipsicóticos con un perfil farmacológico óptimo, más seguros y eficaces.
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