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

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

MeSH terms

  • Allosteric Regulation
  • Amino Acid Sequence
  • Binding Sites
  • Humans
  • Ligands
  • MAP Kinase Kinase Kinases / antagonists & inhibitors
  • MAP Kinase Kinase Kinases / classification
  • MAP Kinase Kinase Kinases / metabolism*
  • Molecular Dynamics Simulation
  • Phylogeny
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / metabolism*
  • Protein Structure, Secondary
  • Protein Structure, Tertiary

Substances

  • Ligands
  • Protein Kinase Inhibitors
  • MAP Kinase Kinase Kinases