Structure- and Ligand-Based Modeling of Beta-Secretase 1 (BACE1) Inhibitors

There exists a broad consensus among the Alzheimer's disease research community that the key to successful treatment lies in the specific inhibition of beta-amyloid converting enzyme 1 (BACE1). A series of transition-state analogues of BACE1 inhibitors containing fused aryl or biaryl moieties were designed computationally to probe the S2 pocket of BACE1, synthesized, and tested for inhibitory activity. The structure-activity relationship of these inhibitors will be discussed. It has been shown that unlike the bi-aryl, the fused-ring moiety is successfully accommodated in the binding site resulting in ligands with excellent inhibitory activity. When mouse neuroblastoma cells (N2a) are treated with active BACE1 inhibitors 5b and 5c, a reduction in Aβ40 production, c.a. 65% and 35% respectively, compared to the control, was observed. To get additional insights into BACE1 ligand design, we have developed a quantitative structure activity relationship (QSAR) for ‘non-peptidomimetic' BACE1 inhibitors using comparative molecular field analysis (CoMFA). The reported 3D-QSAR model is statistically significant thereby demonstrating a sound SAR for inhibitors that bind to the catalytic site of BACE1. For CoMFA analysis, the statistical parameters are: R2NV = 0.98, R2CV = 0.64, R2LOO = 0.67, SEE = 0.154, F = 287.219 and R2PRED = 0.74. This model should be useful for the identification, design and development of potential BACE1 inhibitors.