Proton-Coupled Conformational Allostery Modulates the Inhibitor Selectivity for β-Secretase.

ABSTRACT: Many important pharmaceutical targets, such as aspartyl proteases and kinases, exhibit pH-dependent dynamics, functions and inhibition. Accurate prediction of their binding free energies is challenging because current computational techniques neglect the effects of pH. Here we combine free energy perturbation calculations with continuous constant pH molecular dynamics to explore the selectivity of a small-molecule inhibitor for β-secretase (BACE1), an important drug target for Alzheimer's disease. The calculations predicted identical affinity for BACE1 and the closely related cathepsin D at high pH; however, at pH 4.6 the inhibitor is selective for BACE1 by 1.3 kcal/mol, in excellent agreement with experiment. Surprisingly, the pH-dependent selectivity can be attributed to the protonation

SUBMITTER: Harris RC 

PROVIDER: S-EPMC5713904 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature