Estudos computacionais de ligantes dos receptores nicotínicos de acetilcolina do subtipo α4β2
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Data
2019-02-26
Autores
Batista, Victor de Sousa [UNESP]
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Universidade Estadual Paulista (Unesp)
Resumo
Os nAChRs (receptores nicotínicos de acetilcolina) são canais iônicos pentaméricos que respondem ao neurotransmissor endógeno acetilcolina, com os subtipos α4β2 e α7 sendo expressos em grandes quantidades no cérebro humano. Esses receptores estão envolvidos em desordens neurológicas como a doença de Alzheimer, esquizofrenia, dor crônica e autismo, bem como no vício em nicotina. Neste contexto, o SBDD (structure-based drug design) é uma ferramenta poderosa para o desenvolvimento de novos candidatos à fármacos visando estes receptores. Neste trabalho, aplicou-se a metodologia dbCICA (docking-based comparative intermolecular contacts analysis) para a identificação das condições de ancoragem molecular ótimas para estes dois receptores. Em resumo, compostos bioativos atuando em cada um dos dois receptores foram coletados da literatura científica e ancorados nos receptores α4β2 e α7, explorando diferentes condições de ancoragem. Em seguida, os resultados foram pós-processados através da metodologia dbCICA, uma abordagem baseada em algoritmo genético, visando a identificação de contatos críticos para o reconhecimento molecular entre os ligantes ancorados e os resíduos do sítio ativo. Através dessa análise, foi possível determinar as condições ótimas de ancoragem para ambos os receptores trabalhados. Os contatos críticos identificados através do dbCICA estão em acordo com relatos da literatura sobre interações críticas dessa classe de receptores. As condições ideais de ancoragem para o receptor α4β2 foram utilizadas para selecionar 8 dentre 116 fragmentos moleculares inéditos com potencial atividade biológica frente ao mesmo para serem sintetizados em etapas futuras. Utilizando os dados obtidos para o subtipo α4β2 também foi possível construir um mapa farmacofórico, validado através da curva ROC (receiver operating characteristic curve), que pode ser utilizado em triagens virtuais subsequentes e também em uma posterior etapa de incrementação estrutural. Além disso, foi possível triar 8 fragmentos moleculares inéditos, a partir dos mesmos 116, utilizando as condições de ancoragem ótimas identificadas para o receptor α7 com o intuito de avaliar a possibilidade de seletividade ou atividade dual.
The nAChRs (nicotinic acetylcholine receptors) are pentameric ligand-gated ionic channels that respond to the endogenous neurotransmitter acetylcholine, with the α4β2 and α7 subtypes highly expressed in human brain. Those receptors are involved in many neurologic disorders such as Alzheimer’s disease, Schizophrenia, chronic pain, autism, as well as in nicotine addiction. In this context, SBDD (structure-based drug design) is a powerful tool for designing novel drug candidates targeting those receptors. In this work, we applied dbCICA (docking-based comparative intermolecular contacts analysis) to identify optimal docking conditions for these two receptors. Briefly, bioactive compounds acting on each receptor were gathered from the scientific literature and docked into the binding sites of the α4β2 and α7, exploring different docking conditions. Then, the results were post-processed through dbCICA, a genetic algorithm based approach, aiming to identify critical contacts for molecular recognition involving the docked ligands and binding site residues. Through this analysis it was possible to determine the optimal docking conditions for both receptors. The critical contacts identified by dbCICA are in agreement with the literature about critical interactions from this class of receptors. The optimal docking conditions for receptor α4β2 were used to select 8 from 116 novel molecular fragments with potential biological activity towards this subtype, to be synthesized in future steps. Using the outputs from subtype α4β2 it was possible to build a pharmacophoric map, validated by ROC curve (receiver-operating characteristic curve), which can be applied to further virtual screening and also in a fragment growth step latter on. Also, it was possible to select 8 from the same 116 novel molecular fragments using the optimal docking conditions for α7 nAChR aiming to evaluate if selectivity is possible, as well as dual activity.
The nAChRs (nicotinic acetylcholine receptors) are pentameric ligand-gated ionic channels that respond to the endogenous neurotransmitter acetylcholine, with the α4β2 and α7 subtypes highly expressed in human brain. Those receptors are involved in many neurologic disorders such as Alzheimer’s disease, Schizophrenia, chronic pain, autism, as well as in nicotine addiction. In this context, SBDD (structure-based drug design) is a powerful tool for designing novel drug candidates targeting those receptors. In this work, we applied dbCICA (docking-based comparative intermolecular contacts analysis) to identify optimal docking conditions for these two receptors. Briefly, bioactive compounds acting on each receptor were gathered from the scientific literature and docked into the binding sites of the α4β2 and α7, exploring different docking conditions. Then, the results were post-processed through dbCICA, a genetic algorithm based approach, aiming to identify critical contacts for molecular recognition involving the docked ligands and binding site residues. Through this analysis it was possible to determine the optimal docking conditions for both receptors. The critical contacts identified by dbCICA are in agreement with the literature about critical interactions from this class of receptors. The optimal docking conditions for receptor α4β2 were used to select 8 from 116 novel molecular fragments with potential biological activity towards this subtype, to be synthesized in future steps. Using the outputs from subtype α4β2 it was possible to build a pharmacophoric map, validated by ROC curve (receiver-operating characteristic curve), which can be applied to further virtual screening and also in a fragment growth step latter on. Also, it was possible to select 8 from the same 116 novel molecular fragments using the optimal docking conditions for α7 nAChR aiming to evaluate if selectivity is possible, as well as dual activity.
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Palavras-chave
Química medicinal, Receptores nicotínicos, Canais iônicos, Estudos de validação, Algoritmos genéticos