Insights From Molecular Dynamics Simulations of a Number of G-Protein Coupled Receptor Targets for the Treatment of Pain and Opioid Use Disorders

Abstract

Effective treatments for pain management remain elusive due to the dangerous side-effects of current gold-standard opioid analgesics, including the respiratory depression that has led to skyrocketing death rates from opioid overdoses over the past decade. In an attempt to address the horrific opioid crisis worldwide, the National Institute on Drug Abuse has recently proposed boosting research on specific pharmacological mechanisms mediated by a number of G protein-coupled receptors (GPCRs). This research is expected to expedite the discovery of medications for opioid overdose and opioid use disorders, leading toward a safer and more effective treatment of pain. Here, we review mechanistic insights from recent all-atom molecular dynamics simulations of a specific subset of GPCRs for which high-resolution experimental structures are available, including opioid, cannabinoid, orexin, metabotropic glutamate, and dopamine receptor subtypes.

Keywords: GPCRs; molecular dynamics; opioid crisis; opioid use disorder; pain.

FIGURE 1

A comparison of the representative conformation of the most probable metastable state within an intermediate region of (A) the morphine-bound MOP receptor, where the intermediate state is in light blue, and (B) the TRV-130-bound MOP receptor, where the intermediate state is in light purple, relative to the experimentally determined MOP receptor inactive and active states (light and dark gray, respectively). Note that the most dramatic differences between these conformations stem from the extent of outward movement of TM6 away from TM3, which is one of the most notable conformational changes that has been associated with receptor activation. Images on the right correspond to a 90° rotation of the receptor helical bundle, and represent the view from the intracellular domain.

FIGURE 2

A cartoon representation of the effects of different ligands on a GPCR. The cooperativity between allosteric and orthosteric ligands can shift their affinities for the receptor, and/or bias the GPCR coupling to a particular intracellular partner.

FIGURE 3

The experimentally determined high-resolution GPCR structures, together with their bound ligands, used in the MD-based studies discussed in this review. Nanobodies and other interacting proteins were removed. PDB 4dkl, The antagonist β-FNA bound to the MOP receptor; PDB 5c1m, The agonist BU72 bound to the MOP receptor; PDB 4djh, The antagonist JDTic bound to the KOP receptor; PDB 6b73, The agonist MP1104 bound to the KOP receptor; PDB 4ea3, The peptide mimetic antagonist compound 24 bound to the NOP receptor; PDB 5tgz, The antagonist AM6538 bound to the CB1 receptor; PDB 5xra, The agonist AM11542 bound to the CB1 receptor; PDB 5u09, The inverse agonist taranabant bound to the CB1 receptor; PDB 4s0v, The antagonist suvorexant bound to the OX2 receptor; PDB 3pbl, The antagonist eticlopride bound to the D3 receptor; PDB 4or2, The negative allosteric modulator FITM bound to the transmembrane domain of mGluR1; PDB 4oo9, The negative allosteric modulator mavoglurant bound to the transmembrane domain of mGluR5; PDB 5cgc, The negative allosteric modulator 3-chloro-4-fluoro-5-[6-(1H-pyrazol-1-yl)pyrimidin-4-yl]benzonitrile bound to the transmembrane domain of mGluR5; PDB 5cgd, The negative allosteric modulator 3-chloro-5-[6-(5-fluoropyridin-2-yl)pyrimidin-4-yl]benzonitrile bound to the transmembrane domain of mGluR5.

FIGURE 4

The two energetically most favorable binding modes of the allosteric modulator BMS-986187 – colored yellow and cyan – at the DOP receptor in complex with the orthosteric ligand SNC-80, which is colored in gray. In sticks are the DOP receptor residues in the putative DOP allosteric site used in mutagenesis experiments to help validate the most likely binding mode. The plots to the right show the effect of mutations on the affinity of the allosteric ligand (top right), the induced changes in affinity of the orthosteric ligand (middle plot), and the changes in orthosteric ligand efficacy when the allosteric ligand is bound (bottom right). The experimental data support the predicted BMS-986187 binding mode in cyan color as the most favorable one. Astars indicate the statistical significance levels as given by Dunnet’s test p values (^∗p < 0.05, ^∗∗p < 0.01, and ^∗∗∗p < 0.001).