Planejamento de novos inibidores da enzima Acetilcolinesterase a partir da Galantamina para o tratamento da doença de Alzheimer

Abstract

Alzheimer's disease (AD) is an irreversible neurodegenerative condition that compromises several cognitive functions, including memory, language and self-care ability. Acetylcholinesterase (AChE) inhibitors have shown efficacy in mitigating AD symptoms, although some drugs have cholinergic side effects, such as nausea and vomiting, which can lead to discontinuation of treatment by patients. In this context, this study aimed to select compounds with inhibitory activity on human AChE (hAChE) described in the literature, identify the pharmacophoric region through molecular modeling and, subsequently, validate this model for use in virtual pharmacophore-based screening. Metabolism prediction, with metabolites M3-2, which is formed by the glutathione reaction (Phase II), M1-2 and M2-2 formed by the S-oxidation and aliphatic hydroxylation reaction (Phase I), were both reactive, but without side effects. Theoretical synthetic routes and synthetic accessibility prediction for the most promising compounds are also proposed. In conclusion, in silico modeling can be used for novel drug candidate inhibitors for hAChE. Compounds ZINC16951574-LMQC2 and ZINC08342556-LMQC5 are particularly promising for oral administration because they have a favorable drug-likeness profile, excellent lipid solubility, high bioavailability, and adequate pharmacokinetics