Combined structure and ligand-based design of dual BACE-1/GSK-3β inhibitors for Alzheimer’s disease

Abstract

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder that leads to progressive mental, behavioral, and functional decline including learning ability. The extracellular deposition of amyloid-β (Aβ) peptide as diffused and neuritic plaques and hyper-phosphorylation of tau (p-tau) protein accumulated intracellularly as neurofibrillary tangles (NFTs) are considered to be the major pathological hallmarks occurring in the AD brain. Designing of drugs hitting more than one target against multifactorial diseases, like AD, is one of the worthwhile approach in the drug discovery. Identifying the compounds with computer-aided drug design (CADD) significantly saves the limited resources and accelerates the drug development cycles. The enzymes, BACE-1 and GSK-3β are involved in the initiation of Aβ production through the cleavage of extracellular domain of APP and phosphorylation of various substrates, respectively, leading to the cognitive deficiencies in AD. Thus, targeting BACE-1 and GSK-3β involved in distinct pathological conditions, with single inhibitor, could be conducive approach. In this study, combined structure and ligand-based in silico approach were used to identify potential dual targeting inhibitors. The structure and pharmacophore-based virtual screening, homology modeling, molecular docking, drug-likeness, ADME properties prediction, toxicity risk assessment analysis and molecular dynamics studies were performed to obtain the potential inhibitors. The identified dual inhibitors, i.e., ZINC225531247 and ZINC668197980, are expected to be good leads against BACE-1 and GSK-3β. Graphical abstract: [Figure not available: see fulltext.]. © 2022, Institute of Chemistry, Slovak Academy of Sciences.