Virtual screening identifies ChEMBL3667410, ChEMBL3667414, and ChEMBL3976114 as potent BACE1 inhibitors.

Alzheimer's disease (AD) remains a formidable global health challenge, with no definitive cure. A key pathological hallmark is the accumulation of amyloid-β (Aβ) peptides, which are generated by the proteolytic cleavage of amyloid precursor protein (APP). β-site amyloid precursor protein cleaving enzyme 1 (BACE1), also known as β-secretase, initiates this process and is considered a prime therapeutic target. Current standard-of-care treatments for AD primarily address symptoms, highlighting an urgent need for disease-modifying interventions that target Aβ production.

Researchers performed ligand-based virtual screening (LBVS) on approximately 16 million small molecules, using the clinical-stage BACE1 inhibitor LY3202626 (IC50 = 0.615 nM) as a reference. Lead candidates were then subjected to ensemble molecular docking to assess binding affinities to BACE1. Molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) analysis was used to quantify binding free energies. Finally, molecular dynamics (MD) simulations were conducted to evaluate the structural stability, residual fluctuations, and conformational changes of BACE1 upon binding with the identified compounds compared to apo-BACE1 and BACE1-LY3202626 complexes.