In Silico Evaluation of the Effect of Geometrical Con guration and Charge of Opioid Antagonists on Their Binding to Opioid Receptors

The effect of the geometric configuration and charge of molecules of opioid receptor (OR) agonists and antagonists on binding to mu-, delta-, and kappa-opioid receptors was studied using the molecular docking method. For the docking procedure, we used the three-dimensional structures of the ligands obtained by X-ray diffraction analysis and available in the Cambridge Crystallographic Data Centre (CCDC), as well as their three-dimensional models built in a molecular editor. The three-dimensional crystal structure of nalmefene, which is absent from the CCDC database, was obtained for the first time in the presented study by X-ray diffraction analysis. Protonated and deprotonated forms of the ligands were tested. The results of the study using the example of morphine, codeine, naloxone, naltrexone, and nalmefene showed that the method of obtaining three-dimensional geometric structures of OR ligands has no effect on the calculated values of the free energy of binding G, which indicates the possibility of using ligand models constructed in silico in computational experiments. The protonation state of the ligand molecule, on the contrary, has a significant effect on the free energy of binding to OR, which can affect the properties of this group of drugs when pH values in the body change. When considering the peculiarities of binding of opioid enantiomers into the ligand-binding center of mu-opioid receptors using the example of morphine, it was shown that (-)-morphine and (+)-morphine share a common site for the cationic group, and not for the phenolic hydroxyl, as was previously assumed. At the same time, studies have shown that molecular docking only partially allows describing the pharmacological action of analgesics and their antagonists. For some substances, such as codeine and synthetic (+)-morphine, in silico experiments there was an overestimation of the effectiveness of the interaction of the drug with the OR, which requires continued improvement of the corresponding calculation methods and models.