Molecular Modeling of µ Opioid Receptor Ligands with Various Functional Properties: PZM21, SR-17018, Morphine, and Fentanyl-Simulated Interaction Patterns Confronted with Experimental Data.

Sabina Podlewska,Andrzej J Bojarski,Ryszard Przewlocki,Lucja Kudla,Ryszard Bugno

doi:10.3390/molecules25204636

Sabina Podlewska, Andrzej J Bojarski + Show 3 more

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https://doi.org/10.3390/molecules25204636

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Abstract

Molecular modeling approaches are an indispensable part of the drug design process. They not only support the process of searching for new ligands of a given receptor, but they also play an important role in explaining particular activity pathways of a compound. In this study, a comprehensive molecular modeling protocol was developed to explain the observed activity profiles of selected µ opioid receptor agents: two G protein-biased µ opioid receptor agonists (PZM21 and SR-17018), unbiased morphine, and the β-arrestin-2-biased agonist, fentanyl. The study involved docking and molecular dynamics simulations carried out for three crystal structures of the target at a microsecond scale, followed by the statistical analysis of ligand–protein contacts. The interaction frequency between the modeled compounds and the subsequent residues of a protein during the simulation was also correlated with the output of in vitro and in vivo tests, resulting in the set of amino acids with the highest Pearson correlation coefficient values. Such indicated positions may serve as a guide for designing new G protein-biased ligands of the µ opioid receptor.

Highlights

IntroductionThe majority of them, including morphine, produce side effects limiting their use, such as respiratory depression, constipation, and addiction
Opioids are effective analgesics widely used for severe pain treatment
BU72 to (a) crystal structures—green: co-crystallized conformation, yellow: ligand orientation (b) 5C1M crystal structures—green: co-crystallized conformation, yellow: ligand orientation obtained obtained in docking

Summary

Introduction

The majority of them, including morphine, produce side effects limiting their use, such as respiratory depression, constipation, and addiction. One of the most interesting approaches is based on the observation that an opioid acting via the μ opioid receptor may activate intracellular signal pathways with varying strength. These ideas of so-called biased signaling or functional selectivity suggest that some opioids may activate the G protein signal pathway and mediate the analgesic effect via the μ opioid receptor and avoid stimulation of the β-arrestin-2 pathway (which seems to be involved in the observed side effects [1]) at the same time. The main interest in the case of the μ opioid receptor ligands is focused on the synthesis of opioid

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