Design of a new potent Alzheimer's disease inhibitor based on QSAR, molecular docking and molecular dynamics investigations

Abstract

A series of 32 molecules derived from 7-prenyloxy-2,3-dihydroflavanone and 5‑hydroxy-7-prenyloxy-2,3-dihydro-flavanone possessing an inhibitory activity against the Acetylcholinesterase (AChE) enzyme were studied using the structure-activity (QSAR) investigations. Electronic descriptors of studied molecules were calculated using Gaussian software using DFT method at the B3YP/6–31G(d, p) level. In addition, constitutional, physicochemical, and topological descriptors were calculated using Chem3D software.The best model obtained by the multiple linear regression (MLR) method was subjected to external and internal statistical validations. What is more, the applicability domain (ad) has been defined for the built model using Williams plot. We have designed new molecular structures similar to the basis of giving of the studied dataset and their activity is predicted by the built model. Then, the molecular docking was used to predict the affinity between the newly inhibitors candidates and the AChE protein. This study was completed by the molecular dynamic simulation (MDs) to predict the stability of the formed complexes, the RMSD and RMSF plots of studied complexes were analyzed.