Estudos computacionais envolvendo os receptores nicotínicos de acetilcolina dos subtipos α4β2, α3β4 e α7 através da análise comparativa de contatos intermoleculares baseada em ancoragem molecular (dbCICA)
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Data
2022-12-20
Autores
Batista, Victor de Sousa [UNESP]
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Editor
Universidade Estadual Paulista (Unesp)
Resumo
Os receptores nicotínicos de acetilcolina são canais iônicos pentaméricos que respondem ao neurotransmissor endógeno acetilcolina, com os subtipos α3β4, α7 e α4β2 sendo expressos em majoritariamente no sistema nervoso central humano. Esses receptores estão envolvidos em desordens neurológicas como a doença de Alzheimer e Parkinson, bem como na dependência em nicotina. Este trabalho descreve a utilização da análise comparativa de contatos intermoleculares baseada em ancoragem molecular para o estudo das características essenciais para o reconhecimento molecular de ligantes do sítio ortostérico dos receptores nicotínicos de acetilcolina do subtipo α3β4 e do sítio alostérico transmembranar dos nAChRs do subtipo α7 da espécie humana. A metodologia consiste em uma etapa de pós processamento dos dados de ancoragem molecular, utilizando um algoritmo genético que visa identificar quais combinações de contatos críticos são essenciais para a explicação da variação de bioatividade observada nos dados de docagem. Os dados produzidos, em conjunto com informações disponíveis na literatura científica, foram utilizados para racionalizar quais interações químicas podem ser maximizadas, com o intuito de produzir compostos com alta afinidade pelos receptores em questão. Utilizaram-se também os dados dos modelos dbCICA para a construção de mapas farmacofóricos, que foram validados através de curva ROC e subsequentemente utilizados na triagem virtual de compostos do banco de dados ZINC, resultando na identificação de ligantes em potencial. Ademais, um mapa farmacofórico previamente construído e validado para o sítio ortostérico ortodoxo, localizado na interface α4-β2 presente na isoforma (α4)2(β2)3 desse subtipo também foi utilizado para triagem virtual. Os dados obtidos previamente através da metodologia dbCICA para este sítio ortodoxo do subtipo α4β2 foram comparados com estruturas relevantes para a proposta de potenciais mecanismos de seletividade entre o sítio supracitado e o sítio inortodoxo que existe na interface α4-α4 da isoforma (α4)3(β2)2 desse mesmo subtipo.
The nicotinic acetylcholine receptors are pentameric ion channels that respond to the endogenous neurotransmitter acetylcholine, with the α3β4, α7 and α4β2 subtypes being majorly expressed in the human central nervous system. These receptors are involved in neurological disorders such as Alzheimer’s and Parkinson’s diseases, as well as in nicotine addiction. This work describes the application of docking-based comparative intermolecular contacts analysis to the study of the essential characteristics to the molecular recognition of ligands in the orthosteric site of the nicotinic acetylcholine receptors of the α3β4 subtype and of the transmembranar allosteric site of the α7 nAChRs subtype of the human species. The methodology consists of a post-processing of the data obtained through molecular docking using a genetic algorithm which aims to identify which combinations of critical contacts are essential to explain the observed variation of bioactivity from the docking data. The data produced, along with information available in the scientific literature, were used to rationalize which chemical interactions could be maximized in order to produce high affinity compounds targeting those receptors. The data from de dbCICA models was also used to build pharmacophoric maps, which were validated by ROC curve analysis, and then used in a virtual screening campaign of the ZINC database, which resulted in the identification of potential ligands. Furthermore, a previously built and validated pharmacophoric map for the orthodox orthostheric site, located at the interface of the α4-β2 subunits of the isoform, of this subtype was also used for virtual screening. The data previously obtained through dbCICA modelling for this orthodox orthosteric site of the α4β2 subtype were compared to relevant structures to propose potential selectivity mechanisms between the orthodox and unorthodox sites, the latter existing in the α4-α4 interface of the isoform (α4)3(β2)2 of this subtype.
The nicotinic acetylcholine receptors are pentameric ion channels that respond to the endogenous neurotransmitter acetylcholine, with the α3β4, α7 and α4β2 subtypes being majorly expressed in the human central nervous system. These receptors are involved in neurological disorders such as Alzheimer’s and Parkinson’s diseases, as well as in nicotine addiction. This work describes the application of docking-based comparative intermolecular contacts analysis to the study of the essential characteristics to the molecular recognition of ligands in the orthosteric site of the nicotinic acetylcholine receptors of the α3β4 subtype and of the transmembranar allosteric site of the α7 nAChRs subtype of the human species. The methodology consists of a post-processing of the data obtained through molecular docking using a genetic algorithm which aims to identify which combinations of critical contacts are essential to explain the observed variation of bioactivity from the docking data. The data produced, along with information available in the scientific literature, were used to rationalize which chemical interactions could be maximized in order to produce high affinity compounds targeting those receptors. The data from de dbCICA models was also used to build pharmacophoric maps, which were validated by ROC curve analysis, and then used in a virtual screening campaign of the ZINC database, which resulted in the identification of potential ligands. Furthermore, a previously built and validated pharmacophoric map for the orthodox orthostheric site, located at the interface of the α4-β2 subunits of the isoform, of this subtype was also used for virtual screening. The data previously obtained through dbCICA modelling for this orthodox orthosteric site of the α4β2 subtype were compared to relevant structures to propose potential selectivity mechanisms between the orthodox and unorthodox sites, the latter existing in the α4-α4 interface of the isoform (α4)3(β2)2 of this subtype.
Descrição
Palavras-chave
Receptores nicotínicos, Química farmacêutica, Relação estrutura-atividade (Bioquímica), Alzheimer, Doença de, Tabagismo