Structural Determinants for the Binding of Morphinan Agonists to the μ-Opioid Receptor.

Xiaojing Cong,Achim Kless,Markus Wagener,Paolo Carloni,Pablo Campomanes,Inga Schapitz,Thomas Koch,Yaakov Koby Levy

doi:10.1371/journal.pone.0135998

Abstract

Atomistic descriptions of the μ-opioid receptor (μOR) noncovalently binding with two of its prototypical morphinan agonists, morphine (MOP) and hydromorphone (HMP), are investigated using molecular dynamics (MD) simulations. Subtle differences between the binding modes and hydration properties of MOP and HMP emerge from the calculations. Alchemical free energy perturbation calculations show qualitative agreement with in vitro experiments performed in this work: indeed, the binding free energy difference between MOP and HMP computed by forward and backward alchemical transformation is 1.2±1.1 and 0.8±0.8 kcal/mol, respectively, to be compared with 0.4±0.3 kcal/mol from experiment. Comparison with an MD simulation of μOR covalently bound with the antagonist β-funaltrexamine hints to agonist-induced conformational changes associated with an early event of the receptor’s activation: a shift of the transmembrane helix 6 relative to the transmembrane helix 3 and a consequent loss of the key R165-T279 interhelical hydrogen bond. This finding is consistent with a previous proposal suggesting that the R165-T279 hydrogen bond between these two helices indicates an inactive receptor conformation.

Highlights

Opioid drugs, such as morphine, are widely used in clinics for the treatment of acute, postoperative, and chronic pain
During 0.8 μs molecular dynamics (MD) simulations, the transmembrane domain of μ-opioid receptor (μOR) remain relatively rigid (Cα RMSF ranging from 0.4 Å to 1.5 Å) while, as expected, the loop regions of μOR display larger fluctuations (Cα RMSF ranging from 1.0 to 7.1 Å) (S1 Fig)
The largest fluctuations occur in the modeled IL3, the region where a T4-lysozyme is located in the X-ray structure of the receptor, for the case of the HMP-μOR complex (S1 Fig)

Summary

Introduction

Opioid drugs, such as morphine, are widely used in clinics for the treatment of acute, postoperative, and chronic pain. Owing to their exceptional analgesic properties, they are consistently among the most commonly prescribed drugs nowadays [1]. Frequently highly effective, opioids consumption in a regular basis leads to the appearance of undesirable side effects, such as constipation or respiratory depression, which limit their clinical applicability. Their usage often leads to addiction, tolerance and withdrawal [2]. This poses a major problem for the use of the existing opioids in clinics, complicating dosing regimens for patients and strongly restricting the prescription of these drugs [3, 4].

Methods

Results

Conclusion