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PLoS One. 2017 Jun 19;12(6):e0179936. doi: 10.1371/journal.pone.0179936. eCollection 2017.

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

Author information

1
National Center for Biotechnology Information, National Library of Medicine, National Institute of Health, Bethesda, Maryland, United States of America.
2
Department of Computer Science, Hunter College, The City University of New York, New York, United States of America.
3
The Graduate Center, The City University of New York, New York, United States of America.
4
Office of the Director, National Institutes of Health, Bethesda, Maryland, United States of America.

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.

PMID:
28628649
PMCID:
PMC5476283
DOI:
10.1371/journal.pone.0179936
[Indexed for MEDLINE]
Free PMC Article

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