Zhao Hongtao, Caflisch Amedeo
Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
Bioorg Med Chem Lett. 2014 Mar 15;24(6):1523-7. doi: 10.1016/j.bmcl.2014.01.083. Epub 2014 Feb 10.
The non-receptor tyrosine kinase Syk (spleen tyrosine kinase) is a pharmaceutical relevant target because its over-activation is observed in several autoimmune diseases, allergy, and asthma. Here we report the identification of two novel inhibitors of Syk by high-throughput docking into a rare C-helix-out conformation published recently. Interestingly, both compounds are slightly more active on ZAP70 (Zeta-chain-associated protein kinase 70), which is the kinase closest to Syk in the phylogenetic tree of human kinases. Taken together, the docking pose and experimental results suggest that the higher affinity of the inhibitors for ZAP70 than Syk originates from a more populated C-helix-out conformation in ZAP70. The latter observation is congruent with the 100-fold lower intrinsic activity of ZAP70 than Syk, as the C-helix-out conformation is inactive. The pharmacophore features of DFG-in, C-helix-out compounds are analyzed in relation to DFG-out inhibitors.
非受体酪氨酸激酶Syk（脾酪氨酸激酶）是一个与药物研发相关的靶点，因为在多种自身免疫性疾病、过敏和哮喘中都观察到其过度激活。在此，我们报告通过高通量对接进入最近公布的一种罕见的C螺旋向外构象，鉴定出两种新型Syk抑制剂。有趣的是，这两种化合物对ZAP70（ζ链相关蛋白激酶70）的活性略高，而ZAP70是人类激酶系统发育树中与Syk最接近的激酶。综合来看，对接构象和实验结果表明，抑制剂对ZAP70的亲和力高于Syk，这源于ZAP70中更丰富的C螺旋向外构象。后一观察结果与ZAP70的内在活性比Syk低100倍相一致，因为C螺旋向外构象是无活性的。结合DFG-out抑制剂，分析了DFG-in、C螺旋向外化合物的药效团特征。
