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Discovery of Novel Biased Opioid Receptor Ligands through Structure-Based Pharmacophore Virtual Screening and Experiment

Jeong, Pyeonghwa and Kim, Soo-Kyung and Li, Quanjie and Oh, Su-jin and Son, Seonil and Chen, Guangju and Tan, Hongwei and Kim, Siwon and Park, Jong-Hyun and Park, Ki Duk and Kim, Yeo Ok and Yoon, Myung Ha and Kim, Yong-Chul and Goddard, William, III (2019) Discovery of Novel Biased Opioid Receptor Ligands through Structure-Based Pharmacophore Virtual Screening and Experiment. ChemMedChem, 14 (20). pp. 1783-1794. ISSN 1860-7179. doi:10.1002/cmdc.201900418.

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G_i‐protein biased agonists with minimal β‐arrestin recruitment have shown opportunities for alternative safe pain treatment to overcome the serious adverse effects of human mu opioid receptor (μ‐OR) agonists. In order to discover novel non‐morphine OR agonists, we applied hierarchical virtual screening of our in‐house database against a pharmacophore based on modeling the active conformation of ORs.We discovered Initial hit compound (4), a novel μ‐OR agonist with pyrazoloisoquinoline scaffold. We applied computational R‐group screening to compound 4 and synthesized 14 derivatives predicted to be best. Of these, the new Gi‐protein biased compound (19) shows EC50 = 179 nM at μ‐OR. This resulting in significant pain‐relief effects for mice at the phase II period in formalin tests. This study provides a new strategy to identify diverse sets of promising compounds that might prove useful for drug developments targeting other G protein‐coupled receptors (GPCRs).

Item Type:Article
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URLURL TypeDescription
Kim, Soo-Kyung0000-0002-4498-5441
Goddard, William, III0000-0003-0097-5716
Additional Information:© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim. Accepted manuscript online: 30 July 2019; Manuscript accepted: 16 July 2019; Manuscript received: 13 July 2019. Funding Information: Gwangju Institute of Science and Technology; National Research Foundation of Korea. Grant Number: NRF-2018M3A9A7053266; China Scholarship Council.
Funding AgencyGrant Number
Gwangju Institute of Science and TechnologyUNSPECIFIED
National Research Foundation of Korea2018M3A9A7053266
China Scholarship CouncilUNSPECIFIED
Subject Keywords:opioid Gi-biased agonist virtual screening protein construction R-group screening
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Issue or Number:20
Record Number:CaltechAUTHORS:20190731-131005491
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Official Citation:P. Jeong, S.-K. Kim, Q. Li, S.-j. Oh, S. Son, G. Chen, H. Tan, S. Kim, J.-H. Park, K. D. Park, Y. O. Kim, M. H. Yoon, Y.-C. Kim, W. A. Goddard, ChemMedChem 2019, 14, 1783.
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:97555
Deposited By: Tony Diaz
Deposited On:31 Jul 2019 23:04
Last Modified:16 Nov 2021 17:32

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