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Proton-Coupled Conformational Allostery Modulates the Inhibitor Selectivity for ?-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 ?-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 of His45, which allosterically modulates a loop-inhibitor interaction. Allosteric regulation induced by proton binding is likely common in biology; considering such allosteric sites could lead to exciting new opportunities in drug design.

SUBMITTER: Harris RC 

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

REPOSITORIES: biostudies-literature

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

Harris Robert C RC   Tsai Cheng-Chieh CC   Ellis Christopher R CR   Shen Jana J  

The journal of physical chemistry letters 20170921 19


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 diseas  ...[more]

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