Combining dyad protonation and active site plasticity in BACE-1 structure-based drug design

The ability of the BACE-1 catalytic dyad to adopt multiple protonation states and the conformational flexibility of the active site have hampered the reliability of computational screening campaigns carried out on this drug target for Alzheimer's disease. Here, we propose a protocol that, for the first time, combining quantum mechanical calculations, molecular dynamics, and conformational ensemble virtual ligand screening addresses these issues simultaneously. The encouraging results prefigure this approach as a valuable tool for future drug discovery campaigns.