Proton-Coupled Conformational Allostery Modulates the Inhibitor Selectivity for ß-Secretase.
J Phys Chem Lett
; 8(19): 4832-4837, 2017 Oct 05.
Article
en En
| MEDLINE
| ID: mdl-28927275
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 ß-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.
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1
Colección:
01-internacional
Base de datos:
MEDLINE
Idioma:
En
Revista:
J Phys Chem Lett
Año:
2017
Tipo del documento:
Article
País de afiliación:
Estados Unidos
Pais de publicación:
Estados Unidos