Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 13, Issue 20, Pages 3465-3470Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/S0960-894X(03)00733-9
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Death associated protein kinase (DAPK) is a calcium and calmodulin regulated enzyme that functions early in eukaryotic programmed cell death, or apoptosis. To validate DAPK as a potential drug discovery target for acute brain injury, the first small molecule DAPK inhibitor was synthesized and tested in vivo. A single injection of the aminopyridazine-based inhibitor administered 6 h after injury attenuated brain tissue or neuronal biomarker loss measured, respectively, 1 week and 3 days later. Because aminopyridazine is a privileged structure in neuropharmacology, we determined the high-resolution crystal structure of a binary complex between the kinase domain and a molecular fragment of the DAPK inhibitor. The co-crystal structure describes a structural basis for interaction and provides a firm foundation for structure-assisted design of lead compounds with appropriate molecular properties for future drug development. (C) 2003 Elsevier Ltd. All rights reserved.
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