In silico analysis of biased signaling in the serotonin 2A receptor.

Abstract

The 5-HT2A receptor (5HT2AR) is a widely expressed and highly studied subtype of the serotonin receptor family. Many FDA-approved antidepressants and antipsychotics elicit their pharmacological effects through antagonism of 5HT2AR, a class A G protein-coupled receptor (GPCR). However, these drugs suffer from undesired hallucinogenic effects similar to those produced by classic psychedelics such as LSD and psilocybin. The binding of an agonist to 5HT2AR can induce conformational changes in the receptor and activate intracellular signaling through the G protein- and β-arrestin-mediated pathways. Interestingly, like other GPCRs, the 5HT2A receptor has been shown to exhibit biased signaling in which ligands can preferentially activate one pathway over another. A recent structural and pharmacological study demonstrated that β-arrestin biased agonists, such as IHCH-7086, can exhibit antidepressant properties without hallucinogenic effects. Notably, the IHCH-7086-bound receptor revealed altered conformational changes in a set of phenylalanine residues in the orthosteric sites. However, the subsequent signal transduction mechanism and how other residues in the signaling network are altered remain poorly understood. In this study, using molecular dynamics simulations, we investigated the conformational dynamics of the receptor bound to an antagonist, lumateperone (PDB ID: 7WC8), and IHCH-7086 (PDB ID: 7WC9) in the presence or absence of Gq protein. Our results show that the β-arrestin-biased partial agonist produces significant changes at the intracellular receptor-Gq protein interface residue interactions that are unfavorable for the binding. Also, there is a significant difference in the interactions of IHCH-7086 at the orthosteric binding site. Lastly, our network analysis shows differences in communications between residues among the studied receptor-ligand complexes. The knowledge obtained from this study will be used to develop structure-based pharmacophore models to identify high-affinity biased agonists for the 5HT2A receptor as potential therapeutics to treat 5HT2A receptor-related CNS diseases.