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

Masako Okamoto; Kiyoshi Takayama; Tomoko Shimizu; Kazuhiro Ishida; Osamu Takahashi; Toshio Furuya

doi:10.1021/jm901191q

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.

Authors

Masako Okamoto¹, Kiyoshi Takayama, Tomoko Shimizu, Kazuhiro Ishida, Osamu Takahashi, Toshio Furuya

Affiliation

¹ Drug Discovery Department, Research and Development Division, PharmaDesign, Inc., 2-19-8 Hatchobori, Chuo-ku, Tokyo 104-0032, Japan. [email protected]

PMID: 19877644
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