Opioids are widely used to relieve acute and chronic pain. Advances in structural and biophysical biology (among other disciplines) have allowed further investigation of the use and biological effect of various opioids. Those efforts are focusing on reducing the adverse effects they present after high doses, chronic use, and contraindications. Biased agonism in G protein-coupled receptors is characterized by the induced action of an agonist to a particular signaling pathway. In the case of the μ-opioid receptor (the molecular target of a large part of the opioids on the market), the desired therapeutic effects have been associated with the G protein pathway. To contribute to the knowledge about the interaction of biased agonists with the receptor, in this project, using molecular dynamics simulations, we developed computational models of the μ-opioid receptor with an agonist with experimentally reported high bias, and we also analyzed morphine and herkinorin, as controls. The results obtained indicate that residues Q124, N150, W318, H319, C217, C218 and L219 interact with biased ligands, but not with the unbiased agonist. Also, a tendency to adopt different receptor conformations is observed when comparing both groups through receptor clustering and principal component analysis. These results represent a tool in the design of experimental protocols focused on the development of new molecules with reduced adverse effects.

Interaction patterns and induced conformations by biased and unbiased opioid receptor agonists

ACS Fall 2021

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