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Discovery of Novel Biased Opioid Receptor Ligands through Structure-Based Pharmacophore Virtual Screening and Experiment |
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| Authors: | Pyeonghwa Jeong Dr. Soo-Kyung Kim Quanjie Li Su-jin Oh Seonil Son Dr. Guangju Chen Prof. Hongwei Tan Siwon Kim Dr. Jong-Hyun Park Dr. Ki Duk Park Dr. Yeo Ok Kim Prof. Myung Ha Yoon Prof. Yong-Chul Kim Prof. William A. Goddard III |
| Affiliation: | 1. Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, 123 Cheomdan-gwagiro, Buk-gu, 61005 South Korea These authors contributed equally to this work.;2. Materials and Process Simulation Center (MC-139-74), California Institute of Technology, Pasadena, California, 91125 USA These authors contributed equally to this work.;3. Materials and Process Simulation Center (MC-139-74), California Institute of Technology, Pasadena, California, 91125 USA College of Chemistry, Beijing Normal University, Beijing, 100875 P. R. China Institute of Medicinal Biotechnology, Chinese Academy of Medical Science, Beijing, 100050 P. R. China;4. School of Life Sciences, Gwangju Institute of Science and Technology, 123 Cheomdan-gwagiro, Buk-gu, 61005 South Korea;5. College of Chemistry, Beijing Normal University, Beijing, 100875 P. R. China;6. Convergence Research Center for Diagnosis, Treatment, and Care system of Dementia, Korea Institute of Science and Technology (KIST), Seoul, 02792 South Korea Division of Bio-Medical Science and Technology, KIST School, Korea University of Science and Technology, Seoul, 02792 South Korea;7. Convergence Research Center for Diagnosis, Treatment, and Care system of Dementia, Korea Institute of Science and Technology (KIST), Seoul, 02792 South Korea;8. Convergence Research Center for Diagnosis, Treatment, and Care system of Dementia, Korea Institute of Science and Technology (KIST), Seoul, 02792 South Korea Division of Bio-Medical Science and Technology, KIST School, Korea University of Science and Technology, Seoul, 02792 South Korea KHU–KIST Department of Converging Science and Technology, Kyung Hee University, Seoul, 02447 South Korea;9. Department of Anesthesiology and Pain Medicine, Medical School, Chonnam National University, Gwangju, 501-757 South Korea;10. Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, 123 Cheomdan-gwagiro, Buk-gu, 61005 South Korea;11. Materials and Process Simulation Center (MC-139-74), California Institute of Technology, Pasadena, California, 91125 USA |
| Abstract: | Gi-protein-biased agonists with minimal β-arrestin recruitment represent opportunities to overcome the serious adverse effects of human mu opioid receptor (μ-OR) agonists and developing alternative and safe treatments for pain. In order to discover novel non-morphinan opioid receptor agonists, we applied hierarchical virtual screening of our in-house database against a pharmacophore based on modeling the active conformations of opioid receptors. We discovered an initial hit compound, a novel μ-OR agonist with a pyrazoloisoquinoline scaffold. We applied computational R-group screening to this compound and synthesized 14 derivatives predicted to be the best. Of these, a new Gi-protein-biased compound, 1-{5-(3-chlorophenyl)-7,8-dimethoxy-3-[4-(methylsulfonyl)benzyl]-3H-pyrazolo[3,4-c]isoquinolin-1-yl}-N,N-dimethylmethanamine, showed an EC50 value of 179 nm against the μ-OR. This resulted in significant pain relief for mice in the phase II period of formalin response tests. This study provides a new strategy to identify diverse sets of promising compounds that might prove useful for the development of drugs that target other G-protein-coupled receptors. |
| Keywords: | Gi-biased agonists opioids protein construction R-group screening virtual screening |