Opioid Receptors and Protonation-Coupled Binding of Opioid Drugs.

Samo Lešnik,Éva Bertalan,Ana-Nicoleta Bondar,Urban Bren

doi:10.3390/ijms222413353

Abstract

Opioid receptors are G-protein-coupled receptors (GPCRs) part of cell signaling paths of direct interest to treat pain. Pain may associate with inflamed tissue characterized by acidic pH. The potentially low pH at tissue targeted by opioid drugs in pain management could impact drug binding to the opioid receptor, because opioid drugs typically have a protonated amino group that contributes to receptor binding, and the functioning of GPCRs may involve protonation change. In this review, we discuss the relationship between structure, function, and dynamics of opioid receptors from the perspective of the usefulness of computational studies to evaluate protonation-coupled opioid-receptor interactions.

Highlights

Opioid receptors are class A rhodopsin-like G-protein-coupled receptors (GPCRs) expressed in the brain, spinal cord, peripheral neurons, and digestive tract, where they bind peptidic endogenous opioids [1] to mediate cell signaling paths
Since peripheral MORs are largely responsible for the overall analgesic effects of opioids, selectively targeting opioids to these MORs could enable safer treatment of pain [1,14,15,16,17,18], analgesic effects might be insufficient in the case of very painful pathologies, and opioid drugs will need to be protonated in order to bind to the MORs
We review here opioid receptor function with a focus on recent developments from in silico studies of the MOR and opioid drugs that bind to the MOR

Summary

Introduction

Opioid receptors are class A rhodopsin-like G-protein-coupled receptors (GPCRs) expressed in the brain, spinal cord, peripheral neurons, and digestive tract, where they bind peptidic endogenous opioids [1] to mediate cell signaling paths. The first strategy exploits functional selectivity of opioid receptors, such that downstream signaling via G-proteins, instead of β-arrestins, would be activated. A very promising strategy in developing safer opioids is to restrict the activity of opioids to peripheral sensory neurons in injured and inflamed tissue [13]. Since peripheral MORs are largely responsible for the overall analgesic effects of opioids, selectively targeting opioids to these MORs could enable safer treatment of pain [1,14,15,16,17,18], analgesic effects might be insufficient in the case of very painful pathologies, and opioid drugs will need to be protonated in order to bind to the MORs. Modern in silico methods can provide a detailed picture of opioid binding to GPCRs, and help guide the development of safer opioid drugs.

Opioid Receptor Function

Architecture

Opioid Drugs and How They Bind to the MOR

Force-Field Parametrization of Opioid Drugs

Classical Mechanical Computations of Opioid Receptors

Future Directions