Life beyond kinases: structure-based discovery of sorafenib as nanomolar antagonist of 5-HT receptors.
Life beyond kinases: structure-based discovery of sorafenib as nanomolar antagonist of 5-HT receptors.
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DOI：
10.1021/jm300338m
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发表时间：
2012-06-28
影响因子：
7.3
通讯作者：
Huang, Niu
中科院分区：
文献类型：
--
作者：
Lin, Xingyu;Huang, Xi-Ping;Chen, Gang;Whaley, Ryan;Peng, Shiming;Wang, Yanli;Zhang, Guoliang;Wang, Simon X.;Wang, Shaohui;Roth, Bryan L.;Huang, Niu
近年来，人们对计算预测药物分子的新型多药理学非常感兴趣。在这里，我们应用了一个“诱导拟合”的协议，以改善5-HT 2A受体的同源性模型，我们评估这些模型的质量在回顾性虚拟筛选。随后，我们针对最佳诱导拟合5-HT 2A模型计算筛选FDA批准的药物分子，并选择六个最高得分命中用于实验测定。令人惊讶的是，一种众所周知的激酶抑制剂索拉非尼已经显示出意想不到的混杂5-HTR结合亲和力，对5-HT 2A、5-HT 2B和5-HT 2C的Ki分别为1959、56和417 nM。我们初步的SAR探索支持预测的结合模式，并进一步表明索拉非尼是一种新的先导化合物5 HTR配体发现。尽管索拉非尼通过靶向多种激酶产生抗癌作用是众所周知的，但需要仔细设计实验研究以充分理解其“脱靶”5-HTR结合活性是否有助于其治疗功效或其他不期望的副作用。
Of great interest in recent years has been computationally predicting the novel polypharmacology of drug molecules. Here, we applied an “induced-fit” protocol to improve the homology models of 5-HT2A receptor, and we assessed the quality of these models in retrospective virtual screening. Subsequently, we computationally screened the FDA approved drug molecules against the best induced-fit 5-HT2A models, and chose six top scoring hits for experimental assays. Surprisingly, one well-known kinase inhibitor, sorafenib has shown unexpected promiscuous 5-HTRs binding affinities, Ki = 1959, 56 and 417 nM against 5-HT2A, 5-HT2B and 5-HT2C, respectively. Our preliminary SAR exploration supports the predicted binding mode, and further suggests sorafenib to be a novel lead compound for 5HTR ligand discovery. Although it has been well known that sorafenib produces anticancer effects through targeting multiple kinases, carefully designed experimental studies are desirable to fully understand whether its “off-target” 5-HTR binding activities contribute to its therapeutic efficacy or otherwise undesirable side effects.
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