41370-84-7Relevant academic research and scientific papers
Life beyond kinases: Structure-based discovery of sorafenib as nanomolar antagonist of 5-HT receptors
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
, p. 5749 - 5759 (2012/08/29)
Of great interest in recent years has been computationally predicting the novel polypharmacology of drug molecules. Here, we applied an "induced-fita€ 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-HT 2A, 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-targeta€ 5-HTR binding activities contribute to its therapeutic efficacy or otherwise undesirable side effects.
