CaltechAUTHORS
Published October 17, 2019 | Version Supplemental Material
Journal Article Open

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

Creators

  • 1. ROR icon Gwangju Institute of Science and Technology
  • 2. ROR icon California Institute of Technology
  • 3. ROR icon Beijing Normal University
  • 4. ROR icon Chinese Academy of Medical Sciences & Peking Union Medical College
  • 5. ROR icon Korea Institute of Science and Technology
  • 6. ROR icon Korea University of Science and Technology
  • 7. ROR icon Kyung Hee University
  • 8. ROR icon Chonnam National University

Abstract

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).

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.

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Supplemental Material - cmdc201900418-s1-supporting_information_for_accepted_article.pdf

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Additional details

Identifiers

Eprint ID
97555
Resolver ID
CaltechAUTHORS:20190731-131005491

Funding

Gwangju Institute of Science and Technology
National Research Foundation of Korea
2018M3A9A7053266
China Scholarship Council

Dates

Created
2019-07-31
Created from EPrint's datestamp field
Updated
2021-11-16
Created from EPrint's last_modified field

Caltech Custom Metadata

Other Numbering System Name
WAG
Other Numbering System Identifier
1347