Molecular determinants of distinctive opioid receptor subtype affinities.

Abstract

Despite being targeted by over 30% of the drugs available on the market, G-Protein Coupled Receptors (GPCR) have proven to be notoriously difficult to characterize on an atomistic level. While it is known that helix 6 (TM6) movement is necessary for signal transduction, structural details of activation remain elusive and each receptor is generally studied individually, making comparisons between homologous proteins challenging. Given their homology, any newly discovered drug targeting a specific GPCR may be promiscuous, adding work- and cost-intensive dimensions to the drug discovery process. Some of the GPCRs that seem the most appealing as drug targets are opioid receptors. As opioids are potent pain relievers with widespread use and addictive properties, understanding how drugs bind particular opioid receptor subtypes would allow the design of non-addictive derivatives and thus help alleviate the ongoing opioid crisis - in the United States only, it is estimated that 4 million people use opioids recreationally or are dependent on them, with about half overdose-related deaths being related to synthetic opioids. In this work, we have used enhanced-sampling molecular dynamics simulations to explore the conformational dynamics of different subtypes of opioid receptors and uncovered the molecular determinants of their affinity to various endogenous peptides and synthetic opioids. Using enhanced sampling techniques, we have obtained free energy surfaces (FES) of activation of the μ-, κ-, and δ-subtypes. By comparing the metastable states obtained from the FES, we have pinpointed key structural differences relevant to the activation process. These findings will allow the development of simple and accurate structure-activity relationship, which in turn will guide the design of new, less addictive opioids.