Drug Discovery Department, Research & Development Division, PharmaDesign Inc., 2-19-8 Hatchobori, Tokyo 104-0032, Japan.
J Med Chem. 2013 Jun 13;56(11):4236-51. doi: 10.1021/jm400307y. Epub 2013 May 29.
Homology modeling of G-protein-coupled seven-transmembrane receptors (GPCRs) remains a challenge despite the increasing number of released GPCR crystal structures. This challenge can be attributed to the low sequence identity and structural diversity of the ligand-binding pocket of GPCRs. We have developed an optimized GPCR structure modeling method based on multiple GPCR crystal structures. This method was designed to be applicable to distantly related receptors of known structural templates. CXC chemokine receptor (CXCR7) is a potential drug target for cancer chemotherapy. Homology modeling, docking, and virtual screening for CXCR7 were carried out using our method. The predicted docking poses of the known antagonists were different from the crystal structure of human CXCR4 with the small-molecule antagonist IT1t. Furthermore, 21 novel CXCR7 ligands with IC50 values of 1.29-11.4 μM with various scaffolds were identified by structure-based virtual screening.
尽管已经有越来越多的 G 蛋白偶联七跨膜受体（GPCR）晶体结构被解析，但 GPCR 的同源建模仍然是一项挑战。这种挑战可以归因于 GPCR 的配体结合口袋的低序列同一性和结构多样性。我们已经开发了一种基于多个 GPCR 晶体结构的优化 GPCR 结构建模方法。该方法旨在适用于具有已知结构模板的远缘受体。CXC 趋化因子受体（CXCR7）是癌症化疗的潜在药物靶点。我们使用该方法对 CXCR7 进行了同源建模、对接和虚拟筛选。已知拮抗剂的预测对接构象与小分子拮抗剂 IT1t 的人 CXCR4 晶体结构不同。此外，通过基于结构的虚拟筛选，鉴定出了 21 种具有不同支架的新型 CXCR7 配体，其 IC50 值为 1.29-11.4 μM。
