Unveiling the structural insights and inhibitory potential of coumarin-1,2,3-triazole hybrids against BACE1: a promising approach for Alzheimer’s disease therapy

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by amyloid beta (Aβ) plaque accumulation, in which β-secretase (BACE1) plays a central role in the amyloidogenic pathway. Inhibition of BACE1 represents a promising therapeutic strategy; however, effective and safe inhibitors remain limited. This study aimed to identify novel coumarin-1,2,3-triazole hybrids as potential BACE1 inhibitors using comprehensive in silico approaches. Molecular shape and distance-based features derived from co-crystal ligands were used to generate and validate a pharmacophore model through ROC-based area under the curve analysis. A designed library of hybrids underwent pharmacophore-based virtual screening, yielding 92 hits with ≤0.6 RMSD. These compounds were further evaluated via structure-based molecular docking, from which six top candidates were selected, demonstrating superior docking scores relative to reported inhibitors. ADMET and density functional theory analyses indicated favorable pharmacokinetic profiles and electronic properties, highlighting potential reactive sites. The selected compound, CUM-0199, was subsequently validated through a 200 ns molecular dynamics simulation and MMGBSA binding free energy analysis, confirming structural stability and favourable binding affinity toward BACE1. Overall, the findings suggest CUM-0199 as a potential lead candidate for AD therapy, warranting further experimental validation and clinical investigation.