Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
Bioorg Med Chem Lett. 2013 Oct 15;23(20):5721-6. doi: 10.1016/j.bmcl.2013.08.009. Epub 2013 Aug 11.
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.
尽管 ζ 链相关蛋白激酶 70 kDa（ZAP70）在自身免疫性疾病中很重要，但目前报道的其选择性抑制剂却很少。在这里，为了诱导所谓的“看门残基”（Met414）及其旁边的疏水口袋的契合，首先通过激酶结构域的结构比对，将一种有效的 Janus 激酶 2（JAK2）抑制剂对接至 ZAP70 的 ATP 结合位点。然后，通过带有骨架原子约束的显式溶剂分子动力学模拟对复合物的模型进行松弛。通过分子动力学产生的 ZAP70 诱导契合构象的高通量对接揭示了 10 种低微摩尔抑制剂，它们对应于六个不同的化学型。这些 ZAP70 抑制剂中有一个对 JAK2 的 IC50 为 110 nM。
