Structure-Based Survey of the Binding Modes of BACE1 Inhibitors

Abstract

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 8like 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.

Binding of Inhibitors to BACE1 Affected by pH-Dependent Protonation: An Exploration from Multiple Replica Gaussian Accelerated Molecular Dynamics and MM-GBSA Calculations

“…Because of the important role of BACE1 as a target in the treatment of AD, experimental studies are increasingly focused on the determination of inhibitor–BACE1 complex structures and the development of inhibitors that interrupt the cleavage of APP by BACE1 for use in the clinic; ,− these studies will provide rich structural bases for the design of drugs that target BACE1. Through these experimental studies, the alterations and effect of the environmental pH, which certainly disrupts the activity of BACE1, have been described .…”

Discovery of a Potent Dual Inhibitor of Acetylcholinesterase and Butyrylcholinesterase with Antioxidant Activity that Alleviates Alzheimer-like Pathology in Old APP/PS1 Mice

“…Oxidative stress has been also suggested to play a pivotal role in the early stages of AD, as it increases deposition of both Aβ and tau . Accordingly, a number of efforts to curb the progression of AD have focused on the development of drugs reducing oxidative stress, clearing toxic Aβ fibrils and oligomers, or inhibiting the enzyme β-secretase (BACE-1), the first of two enzymes involved in the proteolytic cleavage of the amyloid precursor protein (APP) leading to Aβ production. , Recent failures of these drug candidates in late-stage clinical trials ,, have led to the hypothesis that neither Aβ production and deposition nor oxidative stress should be taken as individual targets. Rather, action on a given target should be combined with further action on other key targets in AD.…”

Effects of Disulfide Bonds on Binding of Inhibitors to β-Amyloid Cleaving Enzyme 1 Decoded by Multiple Replica Accelerated Molecular Dynamics Simulations

“…Modulation of the Aβ cascade via safe and effective inhibition of BACE1 activity has attracted great interest from many researchers, considering potent targets toward BACE1 . Moreover, increasing attention has been directed toward developing efficient inhibitors of BACE1 activity, and great progress has been made. − Despite these successes, the knowledge of binding mechanisms of inhibitors to BACE1 is still insufficient. Thus, it is essential for understanding the structure–activity relationship of BACE1 inhibitors to further explore inhibitor–BACE1 binding modes via multiple channels.…”