Combined ligand and structure-based virtual screening approaches for identification of novel AChE inhibitors

Abstract

The excessive activity of acetylcholinesterase enzyme (AChE) causes different neuronal problems, especially dementia and neuronal cell deaths. Food and Drug Administration (FDA) approved drugs donepezil, rivastigmine, tacrine and galantamine are AChE inhibitors and in the treatment of Alzheimer’s disease (AD) these drugs are currently prescribed. However, these inhibitors have various adverse side effects. Therefore, there is a great need for the novel selective AChE inhibitors with fewer adverse side effects for the effective treatment. In this study, combined ligand-based and structure-based virtual screening approaches were used to identify new hit compounds from small molecules library of National Cancer Institute (NCI) containing approximately 265,000 small molecules. In the present study, we developed a computational pipeline method to predict the binding affinities of the studied compounds at the specific target sites. For this purpose, a text mining study was carried out initially and compounds containing the keyword “indol” were considered. The therapeutic activity values against AD were screened using the binary quantitative structure activity relationship (QSAR) models. We then performed docking, molecular dynamics (MD) simulations and free energy analysis to clarify the interactions between selected ligands and enzyme. Thus, in this study we identified new promising hit compounds from a large database that may be used to inhibit the enzyme activity of AChE.

Comparison of clinically approved molecules on SARS-CoV-2 drug target proteins: a molecular docking study

“…Afterward, the structures were converted into pdbqt format by using AutoDockTools 1.5.6 software, in use for docking calculations with Vina.Molecular docking simulations are a widely used computational method for the initial guess of ligand binding to receptor protein[23]. Autodock Vina 1.1.2 software [24] was 6 used for docking calculations and the exhaustiveness parameter was selected as 8, and 10 modes were generated for each ligand.…”