Identification of death-associated protein kinases inhibitors using structure-based virtual screening.
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).
Okamoto
Masako
M
Drug Discovery Department, Research and Development Division, PharmaDesign, Inc., 2-19-8 Hatchobori, Chuo-ku, Tokyo 104-0032, Japan. okamoto@pharmadesign.co.jp
Takayama
Kiyoshi
K
Shimizu
Tomoko
T
Ishida
Kazuhiro
K
Takahashi
Osamu
O
Furuya
Toshio
T
D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D001665:Binding Sites; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D018360:Crystallography, X-Ray; D064550:Death-Associated Protein Kinases; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007700:Kinetics; D008024:Ligands; D008958:Models, Molecular; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D014584:User-Computer Interface
D051017:Apoptosis Regulatory Proteins; D008024:Ligands; D047428:Protein Kinase Inhibitors; C579096:DAPK1 protein, human; D064550:Death-Associated Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases