Evaluation of some herbal active ingredients with γ-secretase inhibitory potential for Alzheimer's disease by In Silico analysis

This study investigates plant-derived compounds that potentially inhibit the γ-secretase enzyme, among potential treatment methods for Alzheimer's Disease. Ginkgolide B stands out for its high binding affinity particularly with Presenilin-1. Withaferin-A highlights its potential as a γ-secretase inhibitor by demonstrating significant interactions with TRP 203 and LEU 200. EVP-0015962 exhibits positive interactions with residues in APH-1A, indicating potential for further research and providing comparative analyses. Asiatic Acid emerges as a potential γ-secretase inhibitor. Ginsenosides demonstrate strong binding with Presenilin-1. Avagacestat emphasizes its potential as a γ-secretase inhibitor with high binding affinity, especially with LEU 201. Huperzine-A forms significant bonds with both PEN-2 and Presenilin-1 within the γ-secretase complex. Semagacestat demonstrates notable interactions, particularly with TYR 119 in APH-1A. Rosmarinic Acid displays significant interactions with Nicastrin. This comprehensive in silico analysis represents a crucial step in evaluating these plant-derived compounds as potential γ-secretase inhibitors for Alzheimer's Disease. Our study employed molecular docking analyses and affinity value calculations using the AutoDock Vina program to construct 3D complex structures of potential γ-secretase inhibitors with γ-secretase. Prior to molecular docking analysis, final checks were performed via PyMOL. The binding regions and types of interactions of potential inhibitors with γ-secretase were comparatively examined using BIOVIA Discovery Studio software. Total energy calculations for γ-secretase complexes post-docking were conducted using Swiss-Pdb Viewer software. The Absorption, Distribution, Metabolism, Excretion, Toxicological (ADMET) properties of selected molecules were assessed using admetSAR software. Ginkgolide B, Withaferin-A, Asiatic Acid, and Ginsenosides exhibited the highest negative affinities to the active site, while these molecules demonstrated the highest oral bioavailability and intestinal absorption in terms of ADMET properties. They also displayed lower hepatotoxic and nephrotoxic characteristics. The findings obtained serve as a guide for in vitro and in vivo studies, and we believe that molecules exhibiting potential as γ-secretase inhibitors through in silico analysis should undergo more detailed molecular analyses under in vitro and in vivo conditions. Keywords: Alzheimer's Disease, EVP-0015962,Semagacestat, Avagacestat