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Life Beyond Kinases: Structure-Based Discovery of Sorafenib as Nanomolar Antagonist of 5-HT Receptors

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National Institute of Biological Sciences, Beijing, No. 7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China
College of Life Sciences, Beijing Normal University, No. 19 Xinjiekouwai Street, Beijing 100875, China
§ Department of Pharmacology and Division of Medicinal Chemistry and Natural Products, The University of North Carolina, Chapel Hill, North Carolina 27759, United States
BeiGene (Beijing) Co., Ltd., No. 30 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China
Department of Pharmaceutical Sciences, Howard University, Washington, D.C. 20059, United States
*Phone: 86-10-80720645. Fax: 86-10-80720813. E-mail: [email protected]
Cite this: J. Med. Chem. 2012, 55, 12, 5749–5759
Publication Date (Web):June 13, 2012
Copyright © 2012 American Chemical Society

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    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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    The sequence alignment between 5-HT2A and its template β-2 adrenoceptor, the structural descriptors used to evaluate the ketanserin complex system, the chemical structure and docking pose prediction assessment of ketanserin-like and cyproheptadine-like ligands, the ranks and annotated activities of top scored docking hits, the structures and experimental binding data of six FDA approved drugs, the detailed experimental assay protocols, and the chemical synthesis route for sorafenib analogues and their corresponding analysis data. This material is available free of charge via the Internet at

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