Translating the Knowledge of Functional Dynamics Toward Designing Inhibitors of BACE1, a Key Aspartate Protease in Alzheimer’s Disease

Beta-site APP cleaving enzyme 1 (BACE1) which plays a major role in Alzheimer’s disease (AD) is being currently considered as a promising target in AD therapeutics by designing inhibitors against it. But there exists very little information regarding the physiological function of the protein. Many highly potent BACE1 inhibitors failed in the clinical trials due to undesired side effects and toxicity. Thus more research to explore the physiological role of BACE1 is an urgent need. The protein is highly flexible and exhibits significant ligand-induced flexibility which poses a serious challenge in computer-aided drug designing. Recent advances in simulation methods as well as increase in computational resources shed novel insight into the ligand recognition process of BACE1, which stimulates the field of research that deals with devising novel methods to incorporate receptor flexibility in BACE1 for computational drug discovery. This chapter aims to provide up-to-date information of the physiological role of BACE1 as well as its localization and sorting pathways and discuss in details the inherent structural flexibility and ligand-induced motion of BACE1. Also, novel drug designing strategies developed targeting this receptor flexibility has been discussed in critical details which paves the path for developing novel method/algorithm in computational drug discovery of BACE1 inhibitors for AD.