Life beyond kinases: structure-based discovery of sorafenib as nanomolar antagonist of 5-HT receptors

J Med Chem. 2012 Jun 28;55(12):5749-59. doi: 10.1021/jm300338m. Epub 2012 Jun 19.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / pharmacology*
  • Benzenesulfonates / chemistry*
  • Cyproheptadine / chemistry
  • Cyproheptadine / metabolism
  • Cyproheptadine / pharmacology
  • Drug Approval
  • Drug Discovery*
  • Ketanserin / chemistry
  • Ketanserin / metabolism
  • Ketanserin / pharmacology
  • Molecular Dynamics Simulation
  • Niacinamide / analogs & derivatives
  • Phenylurea Compounds
  • Protein Conformation / drug effects
  • Pyridines / chemistry*
  • Receptors, Serotonin / chemistry
  • Receptors, Serotonin / metabolism*
  • Sequence Homology, Amino Acid
  • Serotonin Antagonists / chemistry*
  • Serotonin Antagonists / metabolism
  • Serotonin Antagonists / pharmacology*
  • Sorafenib
  • United States
  • United States Food and Drug Administration / legislation & jurisprudence
  • User-Computer Interface


  • Antineoplastic Agents
  • Benzenesulfonates
  • Phenylurea Compounds
  • Pyridines
  • Receptors, Serotonin
  • Serotonin Antagonists
  • Niacinamide
  • Cyproheptadine
  • Ketanserin
  • Sorafenib