Virtual screening and molecular docking of flavonoid compounds as BACE-1 inhibitors for Alzheimer’s Disease: identification of Betagarin as a promising nutraceutical lead candidate

Alzheimer’s Disease (AD) is a progressive neurodegenerative disorder accounting for 60–70% of dementia cases globally, with the β-site amyloid precursor protein cleaving enzyme-1 (BACE-1) representing one of the most intensively studied therapeutic targets due to its rate-limiting role in amyloid-β (Aβ) peptide production. Despite decades of drug discovery efforts, no approved BACE-1 inhibitor has successfully demonstrated both efficacy and safety in large-scale clinical trials, largely owing to off-target toxicity and poor blood–brain barrier (BBB) permeability. This study presents a multi-tiered structure-based virtual screening of 1,870 flavonoid compounds against the catalytic domain of BACE-1 (PDB ID: 2ZJN) using AutoDock Vina. Ligand preparation was performed with Open Babel v3.1.1, and docking was executed within a 30 × 30 × 30 Å grid box centred on the catalytic aspartyl dyad (Asp32 and Asp228). Drug-likeness was evaluated using Lipinski’s Rule of Five, and in silico toxicity was assessed via the OSIRIS Property Explorer across four risk categories. Betagarin, a natural flavonoid constituent of Beta vulgaris (beetroot), was selected as the primary lead candidate, demonstrating a binding affinity of −9.3 kcal/mol, zero Lipinski violations, a molecular weight of 328.316 Da, a LogP of 3.139, and uniformly low-risk toxicological predictions. These results collectively support Betagarin as a compelling nutraceutical-derived BACE-1 inhibitor with a favourable pharmacokinetic and safety profile. Future in vitro enzymatic assays and in vivo validation studies are warranted to confirm inhibitory efficacy and advance this compound towards preclinical development.