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

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 de...

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Bibliographic Details
Published in:PloS one 2017-06, Vol.12 (6), p.e0179936-e0179936
Main Authors: Zhao, Zheng, Xie, Lei, Bourne, Philip E
Format: Article
Language:English
Subjects:
Activation
Allosteric properties
Allosteric Regulation
Amino Acid Sequence
Binding Sites
Bioinformatics
Biology and Life Sciences
Biomedical engineering
Diseases
Dynamic structural analysis
Dynamical systems
FDA approval
Federal regulation
Folding
Health aspects
Humans
Inhibitors
Kinases
Ligands
MAP Kinase Kinase Kinases - antagonists & inhibitors
MAP Kinase Kinase Kinases - classification
MAP Kinase Kinase Kinases - metabolism
Medicine and Health Sciences
Molecular dynamics
Molecular Dynamics Simulation
Molecular structure
Mutation
National libraries
Pharmacology
Phylogeny
Physical Sciences
Protein kinase
Protein Kinase Inhibitors - chemistry
Protein Kinase Inhibitors - metabolism
Protein kinases
Protein Structure, Secondary
Protein Structure, Tertiary
Proteins
Signal transduction
Simulation
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Summary: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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0179936