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Conception de nouvelles molécules à activité sérotoninergique par des méthodes QSAR et des études de dynamique moléculaire de complexe ligands /récepteur

Abstract : Eager to develop new substances which can present a potential biological activity at the level of the Central Nervous system, we planned to study the Quantitative Structure-Activity Relations (QSAR) on several families of made up 5-HT1A.The objective was to predict the activity and the biological selectivity new ligands 5-HT1A with respect transmembrane neuroreceptor (5-HT1A, alpha1, alpha2, D2). With this intention, 382 compounds resulting from various chemical families (indol, tetralin, chromane, thiochromane, piperazine, etc...) were modelled and superimposed on pharmacophores 5-HT1A. We then, for each molecule, calculated and compared various molecular descriptors representative of the aspect electrostatic, lipophilic, steric and topological. The various tables made up of composed and the descriptors were then studied by statistical analyses as the principal component analysis, the discriminating analysis, the multiple regression and the analysis Partial Least Square. From the best statistical models, the biological activity new ligands was predicted. After the pharmacological synthesis and tests, these predictions appeared precise (average deviation of 1 unit of pIC50). In parallel, a study of molecular dynamics of receiver serotoninergic transmembrane 5-HT1A was undertaken in order to account for the functional importance of these ligands on the level of the electrostatic, steric interactions and lipophilic settings concerned within the active site of the receiver. These studies on a limited number of complexes ligand/receptor were also undertaken in order to include/understand the role of certain functional parts of these ligands, role badly definite hitherto by the other techniques. We also obtained qualitative information on the interactions and the mobility of certain parts of the receiver, inter alia on the transmembrane propellers TMH5, 6 and 7.
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  • HAL Id : tel-00148822, version 1

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Christophe Marot. Conception de nouvelles molécules à activité sérotoninergique par des méthodes QSAR et des études de dynamique moléculaire de complexe ligands /récepteur. Autre. Université d'Orléans, 1995. Français. ⟨tel-00148822⟩

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