Active State-like Conformational Elements in the β₂-AR and a Photoactivated Intermediate of Rhodopsin Identified by Dynamic Properties of GPCRs

G-Protein-coupled receptors (GPCRs) adopt various functionally relevant conformational states in cell signaling processes. Recently determined crystal structures of rhodopsin and the β₂-adrenergic receptor (β₂-AR) offer insight into previously uncharacterized active conformations, but the molecular states of these GPCRs are likely to contain both inactive and active-like conformational elements. We have identified conformational rearrangements in the dynamics of the TM7−HX8 segment that relate to the properties of the conserved NPxxY(x)5,6F motif and show that they can be used to identify active state-like conformational elements in the corresponding regions of the new structures of rhodopsin and the β₂-AR

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, <i>K</i>_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