Identification of death-associated protein kinases inhibitors using structure-based virtual screening

J Med Chem. 2009 Nov 26;52(22):7323-7. doi: 10.1021/jm901191q.

Abstract

Death-associated protein kinases (DAPKs) function in the early stages of eukaryotic programmed cell death. DAPKs are now emerging as targets for drug discovery in novel therapeutic approaches for ischemic diseases in the brain, heart, kidney, and other organs. Using a structure-based virtual screening approach, we discovered potent and selective DAPKs inhibitors. 6 was found to be the most potent inhibitor with enzyme selectivity (IC(50) = 69 nM for DAPK1).

MeSH terms

  • Apoptosis Regulatory Proteins / antagonists & inhibitors*
  • Apoptosis Regulatory Proteins / chemistry
  • Binding Sites
  • Calcium-Calmodulin-Dependent Protein Kinases / antagonists & inhibitors*
  • Calcium-Calmodulin-Dependent Protein Kinases / chemistry
  • Crystallography, X-Ray
  • Death-Associated Protein Kinases
  • Drug Evaluation, Preclinical
  • Humans
  • Kinetics
  • Ligands
  • Models, Molecular
  • Protein Conformation
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology*
  • User-Computer Interface*

Substances

  • Apoptosis Regulatory Proteins
  • Ligands
  • Protein Kinase Inhibitors
  • DAPK1 protein, human
  • Death-Associated Protein Kinases
  • Calcium-Calmodulin-Dependent Protein Kinases

Associated data

  • PDB/1IG1
  • PDB/1P4F
  • PDB/1WVX
  • PDB/1WVY