Discovery of a novel class of non-ATP site DFG-out state p38 inhibitors utilizing computationally assisted virtual fragment-based drug design (vFBDD)

Bioorg Med Chem Lett. 2011 Dec 1;21(23):7155-65. doi: 10.1016/j.bmcl.2011.09.078. Epub 2011 Sep 28.

Abstract

Discovery of a new class of DFG-out p38α kinase inhibitors with no hinge interaction is described. A computationally assisted, virtual fragment-based drug design (vFBDD) platform was utilized to identify novel non-aromatic fragments which make productive hydrogen bond interactions with Arg 70 on the αC-helix. Molecules incorporating these fragments were found to be potent inhibitors of p38 kinase. X-ray co-crystal structures confirmed the predicted binding modes. A lead compound was identified as a potent (p38α IC(50)=22 nM) and highly selective (≥ 150-fold against 150 kinase panel) DFG-out p38 kinase inhibitor.

MeSH terms

  • Adenosine Triphosphate / chemistry
  • Animals
  • Computer Simulation*
  • Crystallography, X-Ray
  • Dexamethasone / pharmacology
  • Drug Discovery*
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors* / chemical synthesis
  • Enzyme Inhibitors* / chemistry
  • Enzyme Inhibitors* / pharmacology
  • Humans
  • Inhibitory Concentration 50
  • Mice
  • Models, Molecular
  • Molecular Structure
  • Oligopeptides / chemistry*
  • Rats
  • Thiophenes* / chemical synthesis
  • Thiophenes* / chemistry
  • Thiophenes* / pharmacology
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors*

Substances

  • DFG peptide
  • Enzyme Inhibitors
  • Oligopeptides
  • Thiophenes
  • Dexamethasone
  • Adenosine Triphosphate
  • p38 Mitogen-Activated Protein Kinases