Biased Agonism at Opioid Receptors: Insights from Analysis of Structural Interaction Fingerprints

Abstract

Biased agonism, that is the ligand-dependent selectivity for specific signaling pathways in a G protein coupled receptor (GPCR), is an emerging, promising strategy for the development of safer drugs. In the case of the kappa opioid receptor (KOPr), its preferential activation of G-protein versus β-arrestin has been proposed to provide a more direct route to discovering non-addictive opioid therapeutics with reduced side effects. In fact, the KOPr-mediated dysphoria that usually accompanies the beneficial analgesic effect of KOPr agonists has recently been attributed to the activation of the p38 mitogen-activated protein kinase pathway, which is believed to follow arrestin recruitment to the activated KOPr. This observation suggests that KOPr agonists that selectively activate the G protein, but do not recruit arrestin, may be more effective analgesics since they would not exhibit the adverse effects triggered by the arrestin pathway.Based on the above, understanding the structural and chemical determinants of biased agonism at the KOPr is highly desirable as it can guide the discovery/design of improved therapeutics. Here, we employ flexible docking of a set of recently characterized functionally selective KOPr ligands to establish a predictive model for G protein-biased agonism at this receptor based on characteristics of modes of interaction between the ligand and the KOPr. We apply the resulting classifier to a large set of established KOPr agonists to assess their ability to preferentially promote G protein coupling, arrestin recruitment, or both.