Structure-Based Design of β-Site APP Cleaving Enzyme 1 (BACE1) Inhibitors for the Treatment of Alzheimer’s Disease

Abstract

The amyloid hypothesis asserts that excess production or reduced clearance of the amyloid-β (Aβ) peptides in the brain initiates a sequence of events that ultimately lead to Alzheimer's disease and dementia. The Aβ hypothesis has identified BACE1 as a therapeutic target to treat Alzheimer's and led to medicinal chemistry efforts to design its inhibitors both in the pharmaceutical industry and in academia. This review summarizes two distinct categories of inhibitors designed based on conformational states of "closed" and "open" forms of the enzyme. In each category the inhibitors are classified based on the core catalytic interaction group or the aspartyl binding motif (ABM). This review covers the description of inhibitors in each ABM class with X-ray crystal structures of key compounds, their binding modes, related structure-activity data highlighting potency advances, and additional properties such as selectivity profile, P-gp efflux, pharmacokinetic, and pharmacodynamic data.

Constant pH Molecular Dynamics Reveals pH-Modulated Binding of Two Small-Molecule BACE1 Inhibitors

“…3 Therefore, in more recent years, small-molecule inhibitors have emerged as a promising route for treatment and prevention of AD. 3 …”

“…Second, the flap, a β -hairpin loop spanning residues Tyr68 to Glu77, lies directly over the catalytic dyad and can open and close at room temperature to allow substrate and inhibitor access to the active site. 3,5 Finally, the 10s loop, a β -hairpin loop with Ser10 at the tip, can adopt an “up” or “down” conformation, modulating the accessibility of an additional binding pocket, which further impacts the inhibitor effectiveness. 6 …”

“…3 These heterocycles are often referred to as the aspartyl binding motif (ABM). However, determining the optimal p K a of the basic amine has been a formidable task.…”

Navigating the Chemical Space of Multitarget-Directed Ligands: From Hybrids to Fragments in Alzheimer’s Disease

“…5 also permeated the brain in mouse pharmacokinetic assessment, a fundamental property for central nervous system (CNS)-directed drugs [51]. The guanidino moiety, a key functionality of several BACE-1 inhibitors, such as acylguanidines and aminoimidazoles, may bind to the catalytic aspartic dyad of BACE-1 [52,53]. Whereas, the amino and carbonyl functionalities of the cyclic amide group may act as H-bond donor and acceptor, respectively, thus forming H-bond interactions with the backbone of the GSK-3β hinge region.…”

Docking and Quantitative Structure Activity Relationship studies of Acyl Guanidines as β-Secretase (BACE1) Inhibitor

“…BACE1 shares sequence homology with BACE2 (52%), cathepsin D (29%), pepsin (27%), cathepsin E (27%), and renin (24%). 16 Therefore, BACE1 inhibitors should not only demonstrate potent activity but also selectivity, good oral bioavailability, blood-brain barrier penetration, and efficacy at a therapeutically acceptable dose. To overcome this challenge, 3D-QSAR approaches have been a strong research tool in medicinal chemistry and critical to induce some rational guidelines for further structural modification.…”