Interconversion of the (+)-O-desmethyltramadol to the lowest-energy conformer when coupled to µ-opioid receptor: comprehensive analysis using in silico molecular modeling.

The µ-opioid receptor (µOR) is one of the most important therapeutic targets for drugs worldwide as it plays a fundamental role in pain modulation. Tramadol interacts effectively with µOR for the treatment of pain, with its metabolite (+)-O-desmethyltramadol (M1) being the main cause of its opioid action. However, the structural and pharmacological differences of M1 with respect to opioids do not allow us to fully understand its functioning in the body. In this work, we contribute to the molecular understanding of the mechanism of action of M1. We conduct an exhaustive computational study that integrates molecular docking and molecular dynamics simulations of the µOR-M1 complex. To achieve a comprehensive analysis, we consider eight different conformations for M1, two chair-type and six twisted boat-type. Our study suggests interconversion from twisted boat-type to chair-type conformations and the factors that drive this interconversion, which are, ligand fluctuations, lack of intramolecular bonds, the effect of solvation and conformational energy barriers. We also conclude that to perform protein-ligand molecular modeling it is necessary to use several techniques to achieve reliable results as in our case. These findings contribute to the design of more effective chemical analogues of tramadol.