Designing highly selective small-molecule compounds is an important challenge in drug discovery. Here we discuss a constant pH molecular dynamics study that explores the selectivities of beta-secretase 1 (BACE1) inhibitors againist the highly similar isoform BACE2. Using a model inhibitor developed by Eli Lily, we found that in the enzyme active pH range, the flap of BACE1 is flexible and a S3 pocket serine forms a water-mediated hydrogen bond network with the deprotonated pyrimidinyl group of the inhibitor. In contrast, the flap of BACE2 remains closed and a S3 pocket threonine forms a direct hydrogen bond with the protonated pyrimidinyl group. These and other simulation findings are in agreement with the most recent medicinal chemistry data and provide rich mechanistic details in support of the hypothesis that the flap and S3 pocket are selectivity hot spots. Our work demonstrates that considering a complex interplay of protein dynamics, binding site water, protein-ligand interactions, and ligand protonation state change can further advance structure-based drug design.<br/><br/>

How binding site water and inhibitor protonation modulate the selectivities of beta-secretase 1 inhibitors

2019 Spring National Meeting

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