Binding Pathways of a G-Protein Biased μ-opioid Receptor agonist under Clinical Evaluation

Abstract

The ability of certain μ-opioid receptor agonists to preferentially activate G protein-dependent over β-arrestin-dependent signaling pathways holds great potential for the design of improved therapeutic agents. In fact, some opioid molecules that exhibit limited arrestin recruitment have been shown to display effective analgesia with reduced adverse effects compared to the classical opioid analgesic morphine. One of these molecules, TRV130, was recently shown to induce less respiratory depression and constipation than morphine, and is currently being evaluated in human clinical trials for acute pain management. To elucidate the molecular determinants responsible for the binding of TRV130 at the μ-opioid receptor, thus informing future design of improved analgesics with reduced adverse effects, we report here multi-microsecond, all-atom molecular dynamics simulations of this ligand binding to the recently disclosed active μ-opioid receptor crystal structure. Analysis of over 45 μs of molecular dynamics simulations of TRV130 provides insight into its binding pathways, including information about several long-lived states of the ligand bound within the so-called extracellular vestibule, and a stable binding mode of the ligand at the accepted orthosteric binding site. Analysis of this predicted bound state reveals testable hypotheses of ligand-receptor interactions that may guide the structure-based design of improved opioid analgesics.