Structure-Based Survey of the Binding Modes of BACE1 Inhibitors

BACE1 is a key aspartic protease that cleaves the amyloid precursor protein to generate of the amyloid peptide that is believed to be responsible for the Alzheimer's disease amyloid cascade. It is thus recognized as a promising therapeutic target for Alzheimer's disease treatment, and large efforts have been made in the discovery of novel BACE1 inhibitors. This Review presents a systematic mining of BACE1 inhibitors based on 354 crystal structures of the BACE1 catalytic domain in complex with ligands in the Protein Data Bank. A thorough exploration on the frequency as well as the patterns of residue-ligand interactions enables us to subdivide the ligand binding pocket into 10 subsites and then identify favorable substructures of ligands for each subsite. In addition, it is found that the assembly of subsites with an 8-like shape is responsible to bind all inhibitors and four major ligand binding modes are revealed. Thus, such a systematic survey deepens our understanding of the structural requirements for establishment of BACE1-ligand interactions that determine the affinity of a ligand to BACE1, which is pivotal for structure-based lead optimization and design of novel inhibitors.