Structure-activity relationship of novel DAPK inhibitors identified by structure-based virtual screening.
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.
Okamoto
Masako
M
Drug Discovery Department, Research & Development Division, PharmaDesign, Inc., 2-19-8 Hatchobori, Chuo-ku, Tokyo 104-0032, Japan. okamoto@pharmadesign.co.jp
Takayama
Kiyoshi
K
Shimizu
Tomoko
T
Muroya
Ayumu
A
Furuya
Toshio
T
D000465:Algorithms; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors*; D019295:Computational Biology; D003198:Computer Simulation; D064550:Death-Associated Protein Kinases; D004353:Drug Evaluation, Preclinical; D008958:Models, Molecular; D008968:Molecular Conformation; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D051017:Apoptosis Regulatory Proteins; D047428:Protein Kinase Inhibitors; D064550:Death-Associated Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases