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

Abstract

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.

Integrated Approaches for Genome-wide Interrogation of the Druggable Non-olfactory G Protein-coupled Receptor Superfamily

“…This approach, which we dubbed "receptorome screening," and which has been extensively described in prior reviews (17,(32)(33)(34), has led us to a number of important discoveries including: the identification of the -opioid receptor as the site of action of the widely abused hallucinogen salvinorin A (35); the discovery that the 5-HT 2B serotonin receptor is the valvulopathy receptor (6); identification of the remarkably complex pharmacology of antipsychotic drugs (36); large-scale validation of cheminformatics predictions (3,22); identification of GPCR as high affinity off-targets of kinase inhibitors (37)(38)(39); and large-scale validation of computationally docked and crystallography-confirmed binding poses (11, 40 -48) As radioligand-based approaches require radioligands with high specific activity and high affinity for their targets, they are not useful for the vast majority of GPCRs, for which such radioligands are unavailable. Additionally, the physical, informatics, and infrastructure requirements required to routinely screen more than a few GPCRs simultaneously using radioligand binding assays are beyond the resources of most academic and industrial laboratories.…”

Identification of Similar Binding Sites to Detect Distant Polypharmacology

“…[164] In fact, very few examples actually exist on the use of these ligandbased methods to predict affinities between molecules and proteins distantly related to any of their already known targets. [17,[19][20][21] In this respect, structure-based methods may complement ligand-based methods to detect distant polypharmacology.…”

In Silico Study of Polypharmacology with Ligand-based Interaction Fingerprint

“…Physics-based docking and sampling techniques facilitate such efforts by providing near-native binding poses for interested small molecules [10,11] . However, in contrast with achievements in identifying novel ligands for the specific protein [12][13][14] , there are few reports with respect to the other side of the coin, which means explore new targets for the specific small-molecule drug [15,16] . This could be partially attributed to the inability of current scoring functions in estimating the entropy contribution as well as desolvation effects, which becomes more severe when estimating the absolute binding free energy for a given drug in context of distinct targets [16] .…”