Computational characterization of the binding mode and mechanism of action of tricyclic small molecules at 5-HT1E and 5-HT1F receptors

5-hydroxytryptamine (serotonin) 1E and 1F receptors (5-HT1E and 5-HT1F, respectively) are highly expressed human G protein-coupled receptors with high sequence identity among themselves and other 5-HT1 receptor subtypes. Although the physiological role of 5-HT1E and 5-HT1F is not fully understood, they are molecular targets of drugs that are effective to treat migraine, depression, and schizophrenia, albeit not without also producing adverse effects. Notably, no selective or high-affinity drugs have been reported for the 5-HT1E receptor to date. Thus, there is widespread interest in understanding at an atomic level of detail how small molecules bind and activate these receptors for the ultimate purpose of designing improved therapeutics. Through computational studies including docking calculations, metadynamics rescoring, and molecular dynamics simulations of cryo-electron microscopy structures, we predict the binding mode and mechanism of action of tricyclic small molecules that are capable of simultaneously activating the 5-HT1E and 5-HT1F receptors. Our results provide testable hypotheses of ligand-receptor interactions and ligand-induced allosteric modulation that may be used to improve the efficacy of these small molecules towards specific biological endpoints.