Investigação in silico do sistema colinérgico: desenvolvimento de antídotos contra armas químicas e prospecção de fármacos para a doença de Alzheimer

Abstract

The cholinergic system plays a central role in both the neurotoxicity induced by organophosphorus compounds (OPs) and the pathophysiology of Alzheimer's disease (AD). Cholinesterases (ChEs) have emerged as important molecular targets for the development of antidotes against neurotoxic chemical agents as well as novel therapeutic strategies for AD. This study aimed to investigate, through in silico approaches, the mechanisms underlying the modulation of human cholinesterases (HssChEs) associated with enzyme reactivation and inhibition. To this end, computational techniques including molecular docking, hybrid quantum mechanics/molecular mechanics (QM/MM) calculations, and molecular dynamics (MD) simulations were employed to evaluate the structural, energetic, and mechanistic properties of different bioactive compounds. The results identified oximes with potential to reactivate OP-inhibited enzymes, as well as promising candidates for acetylcholinesterase (AChE) inhibition in the therapeutic context of AD. Theoretical analyses revealed favorable interactions with the biological targets, conformational stability, and energetic profiles consistent with the expected biological activity. Overall, these findings highlight the value of computational approaches in the rational design of compounds targeting the cholinergic system, contributing to the development of more effective and safer therapeutic and protective strategies.