BACE-1 inhibitors as potential drug candidates for treatment of Alzheimer's disease: a systematic review.

Over the past two decades, intensive research efforts have focused on the discovery and optimization of BACE-1 inhibitors for Alzheimer’s disease treatment, and the development of potent and selective BACE-1 inhibitors remains a central goal. The current review provides an in-depth and systematic analysis of BACE-1 inhibitors with particular emphasis on the mechanistic role of β-secretase in AD. Both 2D and 3D structural features, size, and physicochemical characteristics of the binding pocket of BACE-1 enzyme have been comprehensively examined. The types of molecular interactions required for the development of high-affinity inhibitors within the active-site were analyzed to accommodate diverse chemical scaffolds. Existing therapeutic approaches targeting BACE-1 include monoclonal antibodies and synthetic small-molecule inhibitors at various clinical trial stages. Numerous studies describing the development of new small-molecule inhibitors have also been reported in the literature. A systematic review based on PRISMA guidelines was conducted on these inhibitors, and SAR patterns along with molecular docking studies have been critically analysed. QSAR and ML approaches reported for BACE-1 inhibition are also compiled to highlight the contribution of integrated approaches for accurate activity prediction. Thus, the review provides insights that may accelerate rational lead optimization for novel BACE-1 inhibitors and can assist medicinal chemists in advancing Alzheimer’s therapeutics.