In silico evaluation of the effect of geometrical configuration and charge of opioid antagonists on their binding to opioid receptors

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Abstract

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 ΔG, 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.

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About the authors

D. V. Krivorotov

Research Institute of Hygiene, Occupational Pathology and Human Ecology

Author for correspondence.
Email: denis.krivorotov@bk.ru
Russian Federation, St. Petersburg, 188663

D. A. Belinskaia

Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences

Email: denis.krivorotov@bk.ru
Russian Federation, St. Petersburg, 194223

A. S. Smirnov

St.-Petersburg State University

Email: denis.krivorotov@bk.ru
Russian Federation, Petergof, St. Petersburg, 198504

V. V. Suslonov

St.-Petersburg State University

Email: denis.krivorotov@bk.ru
Russian Federation, Petergof, St. Petersburg, 198504

N. V. Goncharov

Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences

Email: denis.krivorotov@bk.ru
Russian Federation, St. Petersburg, 194223

V. A. Kuznetsov

Research Institute of Hygiene, Occupational Pathology and Human Ecology

Email: denis.krivorotov@bk.ru
Russian Federation, St. Petersburg, 188663

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2. Fig. 1. Geometric configuration of nalmefene according to X-ray diffraction data. a – Structure of nalmefene hydrochloride according to X-ray diffraction data. b – Structure of unprotonated nalmefene according to X-ray diffraction data.

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3. Fig. 2. Interaction of morphine stereoisomers with MOR. a – Conformation of the complex of (–)-morphine with MOR according to electron microscopy data [32]. b – Interaction of optimized deprotonated (–)-morphine with MOR according to molecular docking data. c – Interaction of optimized protonated (–)-morphine with MOR according to molecular docking data. d – Interaction of optimized (green) and crystalline (purple) protonated (–)-morphine with MOR according to molecular docking data. d – Interaction of optimized (+)-morphine with MOR and according to molecular docking data. In the structures obtained by the docking method, the carbon atoms of (–)- and (+)-morphine are highlighted in green or purple, in the structure obtained by electron microscopy, the carbon atoms of (–)-morphine are highlighted in pink. In the experimental structure of the (–)-morphine complex with MOR, hydrogen atoms are absent due to limitations of the method. In the structures obtained by the docking method, minor hydrogen atoms are not shown for clarity of the figure.

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4. Fig. 3. Proposed models of the interaction of morphine enantiomers with sites of the μ-opioid receptor. a – Model in which (–)-morphine and (+)-morphine share a common site for the phenolic hydroxyl [13], b – model in which (–)-morphine and (+)-morphine share a common site for the cationic group.

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5. Fig. 4. Comparative analysis of the interaction of protonated forms of (–)-morphine, (–)-codeine, and (–)-naloxone with MOR according to molecular docking data. a – Conformation of MOR complexes with (–)-morphine (green) and (–)-codeine (purple). b – Conformation of MOR complexes with (–)-morphine (green) and (–)-naloxone (orange). Minor hydrogen atoms are not shown for clarity of the figure.

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6. Fig. 5. Interaction of the protonated form of (–)-morphine with DOR according to molecular docking data. a – Conformation of the (–)-morphine complex with DOR. b – Superposition of the (–)-morphine complexes with MOR and DOR obtained by the molecular docking method. In the (–)-morphine-DOR complex, the carbon atoms of the ligand are highlighted in brown, in the (–)-morphine-MOR complex – in green. In Figure b, the DOR backbone is marked with a gray ribbon, the MOR backbone – with a green ribbon. Minor hydrogen atoms are not shown for clarity of the figure.

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7. Fig. 6. Proposed scheme of interaction of protonated forms of morphine enantiomers with δ-opioid receptor sites.

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8. Fig. 7. Interaction of the protonated form of (–)-morphine with KOR according to molecular docking data. a – Conformation of the (–)-morphine complex with KOR. b – Superposition of the (–)-morphine complexes with MOR and KOR obtained by the molecular docking method. In the (–)-morphine-KOR complex, the carbon atoms of the ligand are highlighted in yellow, in the (–)-morphine-MOR complex – in green. In Figure b, the KOR backbone is marked with a yellow ribbon, the MOR backbone – with a green ribbon. Minor hydrogen atoms are not shown for clarity of the figure.

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