Ensemble Docking of Potential BACE1 Inhibitors for Alzheimer's Disease

Abstract

A wealth of evidence suggests that inhibiting β‐secretase 1 (BACE1) can delay or halt the progression of Alzheimer's disease (AD). Studies have shown that small molecules able to interact with the asp dyad and the flap in the active site of BACE1 can promote inhibition. In our previous published work, six potential BACE1 inhibitors (1–6) were designed, synthesized, and evaluated by pIC50 measures obtained from in vitro FRET inhibition assays. The aim of this work was to implement an in silico ensemble docking approach to study the binding mechanism between 1–6 and flexible conformations of BACE1. We performed a 50 ns molecular dynamics (MD) simulation of a free BACE1 structure to generate an ensemble of flexible BACE1 conformations and docked 1–6 to each conformation in the ensemble. Docking results revealed 3, 5, and 1 exhibiting the most favorable binding affinities across all dockings, while retaining binding orientations relative to the catalytic asp dyad sustained by hydrogen bonds, as well as exhibiting stabilizing hydrophobic and pi‐pi interactions to flap residues. MMGBSA residue decomposition analysis further revealed residues ASP32, ASP228, and TYR71 as the main contributors for binding of 3, 5, and 1 to BACE1. Conversely, 2, 4 and 6 exhibited less favorable binding affinities and as a result formed fewer interactions to critical active site residues responsible for BACE1 inhibition. In addition, the Pearson correlation coefficient (R) values between computational binding affinity and experimental pIC50 values across all dockings, R < −0.75, showed a strong correlation between computational and experimental results. Overall, our computational results support our experimental results, provide crucial information about the binding mechanism behind our potential six BACE1 inhibitors, and highlight the importance of addressing receptor flexibility in docking simulations. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .