Molecular promiscuity, the ability of small molecules and proteins to interact with multiple molecular partners, is both a curse and a boon. The interaction of a pharmaceutical drug with multiple targets on one hand can cause severe side-effects while on the other hand can enhance the therapeutic effects of the drug. It can also provide new insights into the pathophysiology of the disease and open the door for drug repurposing. Molecular promiscuity is quite prevalent amongst G-protein-coupled receptors (GPCRs) and their ligands (1). GPCRs are targets of approximately 35% of all approved drugs (2). Among GPCRs, aminergic receptors, which have been implicated in several mental as well as physiological disorders represent a major drug discovery target class (1, 3). Of particular importance are the 5-HT receptors, which are involved in almost all behavioral and physiological processes, are targets of a large number of drugs, and show considerable molecular promiscuity (1, 2, 3, 4, 5, 6).
My studies have explored three different instances of molecular promiscuity concerning primarily human 5-HT receptors: 1) The interaction of dopamine, an endogenous cognate ligand of dopamine receptors, with the human 5-HT2B and 5-HT2C receptors. 2) The interaction of dobutamine, a synthetic drug targeted at adrenergic receptors, with the human 5-HT2A and 5-HT2B receptors. 3) The interaction of Clozapine, a clinically used antipsychotic, that interacts with several aminergic receptors including 5-HT receptors, with 5-HT2A receptor. I have also examined its potential role in clozapine-induced hyperglycemia, a metabolic side-effect of clozapine treatment. The latter has been carried out in collaboration with my laboratory colleague Dr. Radhika Joshi using a mouse strain, deleted for the 5-HT2A, developed and characterized in our laboratory (7).
The study of the interaction of dopamine with the human 5-HT2B and 5-HT2C receptors revealed that dopamine can activate and desensitize human 5-HT receptors. The potency of dopamine at the 5-HT receptors is lesser than that of 5-HT and so is its affinity for the 5-HT receptors. Molecular docking simulations further revealed that dopamine binds into the presumed orthosteric binding sites in the 5-HT receptors.
The study of the interaction of dobutamine, also a widely used drug, with the human 5-HT2A and 5-HT2C receptors showed that dobutamine, though structurally similar to dopamine, does not activate the 5-HT receptors but surprisingly inhibits them. Molecular docking simulations revealed that dobutamine binds into the presumed orthosteric binding sites of the 5-HT receptors.
The study aimed at examining the potential role of 5-HT2A receptor in clozapine-induced hyperglycemia used a global 5-HT2A receptor knockout mice. Our studies revealed that though Htr2-/- mice showed basal glucose metabolism similar to that of Htr2+/+ mice, they were resistant to the hyperglycemic side effects of single-dose clozapine treatment, unlike Htr2+/+ mice. This was in the presence of similar levels of 5-HT2B and 5-HT2C receptors in peripheral tissues in Htr2-/- mice and Htr2+/+ mice, as determined by examining the presence of their transcripts (8).
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8. Joshi RS, Singh SP, Panicker MM (2019) 5-HT2A deletion protects against Clozapine-induced hyperglycemia. J Pharmacol Sci 139:133–135.
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