Planejamento de candidatos a fármacos multialvo inibidores de Acetilcolinesterase (AChE) e glicogênio sintase quinase-3β (GSK-3β) para tratamento da doença de Alzheimer

Abstract

Introduction: Alzheimer's disease (AD) is characterized by appearance of senile plaques and neurofibillary tangles. Acetylcholinesterase inhibitors (AChEI) and memantine are used as treatment, however, other therapeutic alternatives for AD treatment has been searched, such as Glycogen Synthase Kinase-3β inhibitors (GSK-3βI). Although, one-target drugs can not always modify complex systems, which has several pathological mechanisms. Objectives: Therefore, the aim of this research was to design new AChEI-GSK-3βI multi-target drug candidates for AD treatment. Methodology: Initially, 13 compunds with proven anti-Alzheimer activity were selected. Molecular docking was performed using the GOLD program. Subsequently, pharmacophoric modeling was derived from the PharmaGist webserver. Pharmacokinetic properties were computed using QikProp module of Schrödinger and toxicity profile was evaluated using the DEREK program. Finally, molecular hybridization was performed between the structural subunits of AChEI and GSK-3βI. Results and discussion: In docking study, hydrogen and hydrophobic interactions between AChE and GSK-3β enzymes and selected compounds were observed. In derivation of pharmacophore group, 8 molecules with 3 pharmacophoric points were aligned: one aromatic rings and two hydrogen bond acceptors. Inhibitors demonstrated good pharmacokinetic and toxicological prediction results. After, Physostigmine and Luteolin were chosen as prototypes for design of new AChEI and GSK-3βI drugs candidates. 9 proposals, 5 AChEIs and 4 hybrids AChEI-GSKI-3β were designed. In prediction of biological activity, 9 proposals exhibited anti-Alzheimer activity. In addition, results showed that proposals 1, 2 and 5 obtained the best results in pharmacokinetic and toxicological predictions, still hybrids 6, 7, 8 and 9 presented higher affinity for both AChE and GSK-3β enzymes. Conclusions: Therefore, proposals 1 and 2 and Hybrids 6 and 8 were chosen as potent AChEI and AChEI-GSK-3βI drugs candidates