TY - JOUR KW - Molecular Docking Simulation KW - Protein Binding KW - Binding Sites KW - Hydrophobic and Hydrophilic Interactions KW - Protein Structure, Tertiary KW - Protein Kinase Inhibitors KW - Drug Evaluation, Preclinical KW - High-Throughput Screening Assays KW - Janus Kinase 2 KW - ZAP-70 Protein-Tyrosine Kinase AU - H. Zhao AU - A. Caflisch AB -

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-μM inhibitors which correspond to six distinct chemotypes. One of these ZAP70 inhibitors has an IC50 of 110 nM for JAK2.

BT - Bioorganic & Medicinal Chemistry Letters C1 - 0176 DA - 2013 Oct 15 DO - 10.1016/j.bmcl.2013.08.009 IS - 20 J2 - Bioorg. Med. Chem. Lett. LA - eng M3 - Research Article N2 -

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-μM inhibitors which correspond to six distinct chemotypes. One of these ZAP70 inhibitors has an IC50 of 110 nM for JAK2.

PY - 2013 SP - 5721 EP - 5726 T2 - Bioorganic & Medicinal Chemistry Letters TI - Discovery of ZAP70 inhibitors by high-throughput docking into a conformation of its kinase domain generated by molecular dynamics VL - 23 SN - 1464-3405 ER -