Identifying Modulators of CXC Receptors 3 and 4 with Tailored Selectivity Using Multi-Target Docking
Identifying Modulators of CXC Receptors 3 and 4 with Tailored Selectivity Using Multi-Target Docking
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DOI：
10.1021/cb500577j
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发表时间：
2015-03-01
影响因子：
4
通讯作者：
Kolb, Peter
中科院分区：
文献类型：
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作者：
Schmidt, Denis;Bernat, Viachaslau;Kolb, Peter
C-X-C亚家族的G蛋白偶联受体是趋化因子受体中的一类，其内源性配体是具有共同Cys-X-Cys基序的多肽。本研究中研究的CXC趋化因子受体3和4(CXCR3，CXCR4)与癌症、多发性硬化症和艾滋病毒感染等严重疾病有关。特别令人感兴趣的是，这种受体对可能形成多药物药物治疗的靶点。考虑到公共数据库中已知的配体，这种双重结合还没有被确定。因此，我们对CXCR4的结构和CXCR3的同源模型进行了大规模对接，目的是预测这种双重结合，以及对任一种受体具有选择性的化合物。使用信号和生化分析，我们表明这些预测在每个类别中都超过50%是正确的，产生了具有极好的结合效率的配体。这些结果表明，对接是识别具有定制的GPCRs结合轮廓的配体的合适工具，即使使用同源模型也是如此。更重要的是，我们提出了新的CXCR3-CXCR4双重调节剂，这可能为理解这些受体的多药物抑制机制铺平道路。
The G protein-coupled receptors of the C-X-C subfamily form a group among the chemokine receptors whose endogenous ligands are peptides with a common Cys-X-Cys motif. The CXC chemokine receptors 3 and 4 (CXCR3, CXCR4), which are investigated in this study, are linked to severe diseases such as cancer, multiple sclerosis, and HIV infections. Of particular interest, this receptor pair potentially forms a target for a polypharmacological drug treatment. Considering known ligands from public databases, such dual binders have not been identified yet. We therefore applied large-scale docking to the structure of CXCR4 and a homology model of CXCR3 with the goal to predict such dual binders, as well as compounds selective for either one of the receptors. Using signaling and biochemical assays, we showed that more than 50% of these predictions were correct in each category, yielding ligands with excellent binding efficiencies. These results highlight that docking is a suitable tool for the identification of ligands with tailored binding profiles to GPCRs, even when using homology models. More importantly, we present novel CXCR3-CXCR4 dual modulators that might pave the road to understanding the mechanisms of polypharmacological inhibition of these receptors.