Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 23, Issue 20, Pages 5721-5726Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2013.08.009
Keywords
Tyrosine kinase; High-throughput docking; Molecular dynamics; Autoimmune disease
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Funding
- Swiss National Science Foundation
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Very few selective inhibitors of the zeta-chain associated protein kinase 70 kDa (ZAP70) have been reported despite its importance in autoimmune diseases. Here, to induce a fit of the so-called gatekeeper residue (Met414) and hydrophobic pocket next to it, a potent Janus kinase 2 (JAK2) inhibitor was first docked into the ATP binding site of ZAP70 by structural alignment of the kinase domains. The resulting model of the complex between ZAP70 and the JAK2 inhibitor was then relaxed by an explicit solvent molecular dynamics simulation with restraints on the backbone atoms. High-throughput docking into the induced-fit conformation of ZAP70 generated by molecular dynamics has revealed 10 low-micromolar inhibitors which correspond to six distinct chemotypes. One of these ZAP70 inhibitors has an IC50 of 110 nM for JAK2. (C) 2013 Elsevier Ltd. All rights reserved.
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