Insights into the binding mode of MEK type-III inhibitors. A step towards discovering and designing allosteric kinase inhibitors across the human kinome

Authors

Zheng Zhao, National Institute of Health
Lei Xie, CUNY Hunter CollegeFollow
Philip E. Bourne, National Institutes of Health

Document Type

Article

Publication Date

6-19-2017

Abstract

Protein kinases are critical drug targets for treating a large variety of human diseases. Type- III kinase inhibitors have attracted increasing attention as highly selective therapeutics. Thus, understanding the binding mechanism of existing type-III kinase inhibitors provides useful insights into designing new type-III kinase inhibitors. In this work, we have systematically studied the binding mode of MEK-targeted type-III inhibitors using structural systems pharmacology and molecular dynamics simulation. Our studies provide detailed sequence, structure, interaction-fingerprint, pharmacophore and binding-site information on the binding characteristics of MEK type-III kinase inhibitors. We hypothesize that the helix-folding activation loop is a hallmark allosteric binding site for type-III inhibitors. Subsequently, we screened and predicted allosteric binding sites across the human kinome, suggesting other kinases as potential targets suitable for type-III inhibitors.

Comments

This article originally appeared in PLOS|One, available at https://doi.org/10.1371/journal.pone.0179936

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