Fragment-based Binding Efficiency Indices in Bioactive Molecular Design: A Computational Approach to BACE-1 Inhibitors

One of the most important targets in Alzheimer disease is Beta site amyloid precursor protein cleaving enzyme-1 (BACE-1). It is a membrane associated protein and is one of the main enzymes responsible for amyloid β (Aβ) production. Up to now, a considerable number of peptidic and non-peptidic inhibitors of BACE-1 have been developed. Recently, small molecule BACE-1 inhibitors have attracted the attention of scientists, because peptidic inhibitors have many pharmacokinetic problems. In the present study, several small molecule BACE-1 inhibitors were extracted from Brookhaven Protein Databank (PDB) and subjected to dissection analysis to achieve constructing fragments. Atom type, hybridization, and bond order were considered for generated constitutional fragments (simplified structures). AutoDock version 4.2 was applied to dock various chemical fragments into BACE-1 active site. The benefits of such studies have been well revealed in previous reports. On the basis of obtained binding affinities, fragment-based ligand efficiency (LE) indices were estimated. These theoretical binding efficiencies were applied to further elucidate the key structural features of BACE-1 inhibitors. Typical results of the study were elucidated and we suggested the ways these findings might be beneficial to guide rational bioactive molecular developments. Our study confirmed that the evaluation of ligand-receptor interactions in terms of ligand efficiency indices (binding energy per atom and pKi per MW) could be a helpful strategy in structure-based drug discovery (SBDD) strategies.