Vilazodone-Tacrine Hybrids as Potential Anti-Alzheimer Agents: QSAR, Molecular Docking, and Molecular Dynamic (MD) Simulation Studies

Abstract

Alzheimer's disease (AD) is a type of functional impairment of the brain, which gently degrades the patients' mental potency. The goal pursued in this study is to introduce novel drug candidates as acetylcholinesterase (hAChEIs) and butyl cholinesterase (hBuChE) inhibitors in the treatment of AD. In this study, more than 100 Vilazodone-Tacrin hybrids have been designed to inhibit hAchE and hBuChE. A series of chemical methods such as multiple linear regression (MLR) and GA-PLS were used to create relationships between structural features in these compounds and their hAchE/ hBuChE inhibitory activity. Molecular docking studies against hAChE (PDB ID: 1ACJ) and hBuChE (PDB ID: 4BDS) indicates the important amino acids inside the active site cavity that are responsible of essential interactions were Gly441, Ser122, Trp84, Asp72, Tyr130, and Gly117 for hAChE and Glu197, Thr120, Gly121, Asn83, Tyr332, Trp430, Trp82 and Asp70 for hBuChE. The best regression equation was obtained from GA-PLS, which predicts 92% of variances. Molecular dynamic (MD) simulations were also studied. The reliability, accuracy, and predictability of the proposed QSAR models were evaluated. Finally, an in silico screening study was conducted, and some compounds were introduced as logical candidates as novel anti-Alzheimer agents.