Targeting β -secretase (BACE1) with small-molecule inhibitors offers a promising route for the prevention and treatment of Alzheimer’s disease. However, the intricate pH dependence of BACE1 function and inhibitor efficacy has posed a major challenge for structure-based drug design. In collaboration with our industrial partner MERCK, Graduate student Cheng-Chieh Tsai and postdoctoral associate Chris Ellis investigated two structurally similar BACE1 inhibitors that have dramatically different inhibitory activity using continuous constant pH molecular dynamics (CpHMD), the tool we have been developing in the grant period. This work demonstrates that CpHMD can be used for screening pH-dependent binding profiles of small-molecule inhibitors, providing a new tool for structure-based drug design and optimization.