Life beyond kinases: structure-based discovery of sorafenib as nanomolar antagonist of 5-HT receptors.
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-HT(2A) 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-HT(2A) 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, K(i) = 1959, 56, and 417 nM against 5-HT(2A), 5-HT(2B), and 5-HT(2C), 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.
National Institute of Biological Sciences, Beijing, No. 7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China.
Xingyu
X
Lin
Xi-Ping
XP
Huang
Gang
G
Chen
Ryan
R
Whaley
Shiming
S
Peng
Yanli
Y
Wang
Guoliang
G
Zhang
Simon X
SX
Wang
Shaohui
S
Wang
Bryan L
BL
Roth
Niu
N
Huang
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D001557:Benzenesulfonates / Q000737:chemistry*; D003533:Cyproheptadine / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D017277:Drug Approval; D055808:Drug Discovery; D007650:Ketanserin / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D056004:Molecular Dynamics Simulation; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D011487:Protein Conformation / Q000187:drug effects; D011725:Pyridines / Q000737:chemistry*; D011985:Receptors, Serotonin / Q000737:chemistry / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D012702:Serotonin Antagonists / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D000077157:Sorafenib; D014481:United States; D014486:United States Food and Drug Administration / Q000331:legislation & jurisprudence; D014584:User-Computer Interface
D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D011725:Pyridines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D009536:Niacinamide; D003533:Cyproheptadine; D007650:Ketanserin; D000077157:Sorafenib