AI Article Synopsis
- Current methods for predicting how drugs bind to targets like aspartyl proteases and kinases fail to consider the impact of pH, which is critical for understanding their behavior.
- By combining advanced molecular dynamics with energy calculations, researchers investigated a small-molecule inhibitor for β-secretase (BACE1), showing that its selectivity varied with pH; at low pH, it favored BACE1 over a similar enzyme, cathepsin D.
- The altered selectivity at different pH levels is linked to the protonation of a specific histidine residue (His45), indicating that pH-dependent allosteric interactions could reveal new avenues for drug development.
Article 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 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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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5713904 | PMC |
| http://dx.doi.org/10.1021/acs.jpclett.7b02309 | DOI Listing |
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