Discovery of potentially biased agonists of mu-opioid receptor (MOR) through molecular docking,pharmacophore modeling,and MD simulation |
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| Affiliation: | 1. Key Laboratory of Medicinal Chemistry for Natural Resource (Yunnan University), Ministry of Education, School of Chemical Science and Technology, Yunnan University, Kunming, 650091, People''s Republic of China;2. State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, People’s Republic of China;1. V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences of Ukraine, 02094, Kyiv-94, Murmanska Str,1, Kyiv, Ukraine;2. Nizhyn Mykola Gogol State University, 16600, Grafska Str. 2, Nizhyn, Chernihivska Oblast, Ukraine;3. P.L. Shupyk National Medical Academy of Postgraduate Education, 04112, Dorogozhytska Str, 9, Kyiv, Ukraine;1. Institute for Quantitative Biomedical Sciences, Dartmouth College, Hanover, NH;2. Department of Biomedical Data Science, Geisel School of Medicine, Lebanon, NH;3. Department of Biological Sciences, Dartmouth College, Hanover, NH;4. Department of Epidemiology, Geisel School of Medicine, Lebanon, NH;1. Department of Pharmacology & Toxicology, Virginia Commonwealth University, Richmond, VA, USA;2. Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA, USA;3. Drug Design and Synthesis Section, Molecular Targets and Medications Discovery Branch, NIDA and NIAAA, Bethesda, MD, USA;4. Center for Drug Discovery, Research Triangle Institute, Research Triangle, NC, USA;5. Departments of Molecular Medicine and Neuroscience, The Scripps Research Institute, Jupiter, FL, USA |
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| Abstract: | Opioids are well known for their potent analgesic efficacy and severe side effects. Studies have shown that analgesic effects are mediated by the downstream G-protein-dependent pathway of the μ-opioid receptor (MOR), and another β-arrestin-dependent pathway mediates side effects such as respiratory depression, constipation and tolerance etc. TRV130 is a biased ligand for G-protein-dependent pathway, which has high analgesia and has fewer side effects than morphine. In this study, the structure similarity search was performed on the IBSSC database using Oliceridine (TRV130) and PZM21 as templates. The 3D structure-based pharmacophore model was built and combined molecular docking prediction mode was selected to filter out small molecules, Finally, based on affinity prediction, four candidate molecules were obtained. Molecular dynamics simulations explored the detailed interaction mechanism of proteins with small molecules under dynamics. These results suggest that these candidate molecules are potential MOR agonists. |
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| Keywords: | μ-Opioid receptors (MOR) Biased ligands Molecular docking Hip-hop pharmacophore MD simulation |
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