Structure-activity relationship of novel DAPK inhibitors identified by structure-based virtual screening

Bioorg Med Chem. 2010 Apr 1;18(7):2728-34. doi: 10.1016/j.bmc.2010.02.018. Epub 2010 Feb 15.

Abstract

Death-associated protein kinase (DAPK) is a serine/threonine protein kinase implicated in diverse programmed cell death pathways. DAPK is a promising target protein for the treatment of ischemic diseases. We identified novel potent and selective DAPK inhibitors efficiently by structure-based virtual screening, then further developed the hit compounds. In this paper, we describe the development of the hit compounds and the structure-activity relationship studies of the DAPK inhibitors in detail, including calculation of the solvated interaction energy (SIE), and verification of selectivity using a kinase panel.

MeSH terms

  • Algorithms
  • Apoptosis Regulatory Proteins / antagonists & inhibitors*
  • Calcium-Calmodulin-Dependent Protein Kinases / antagonists & inhibitors*
  • Computational Biology
  • Computer Simulation
  • Death-Associated Protein Kinases
  • Drug Evaluation, Preclinical
  • Models, Molecular
  • Molecular Conformation
  • Protein Binding
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / pharmacology*
  • Structure-Activity Relationship

Substances

  • Apoptosis Regulatory Proteins
  • Protein Kinase Inhibitors
  • Death-Associated Protein Kinases
  • Calcium-Calmodulin-Dependent Protein Kinases