Discovery of biphenylacetamide-derived inhibitors of BACE1 using de novo structure-based molecular design.

摘要: β-Secretase (BACE1), the enzyme responsible for first and rate-limiting step in production of amyloid-β peptides, is an attractive target treatment Alzheimer’s disease. In this study, we report application de novo fragment-based molecular design program SPROUT to discovery a series nonpeptide BACE1 inhibitors based upon biphenylacetamide scaffold. The binding affinity molecules designed scaffold was increased from initial IC50 323 μM 27 following synthesis library optimized ligands whose structures were refined using recently developed SPROUT-HitOpt software. Although number found exhibit cellular toxicity, one compound have useful inhibitory activity assay with minimal toxicity. This work demonstrates power silico approach novel inhibitors.