2. Academic Validation
  3. Docking for EP4R antagonists active against inflammatory pain

Docking for EP4R antagonists active against inflammatory pain

  • Nat Commun. 2023 Dec 6;14(1):8067. doi: 10.1038/s41467-023-43506-6.
Stefan Gahbauer # 1,  Chelsea DeLeon # 2,  Joao M Braz # 3,  Veronica Craik 3,  Hye Jin Kang 2 4,  Xiaobo Wan 1,  Xi-Ping Huang 2,  Christian B Billesbølle 1,  Yongfeng Liu 2,  Tao Che 2 5,  Ishan Deshpande 1,  Madison Jewell 3,  Elissa A Fink 1,  Ivan S Kondratov 6 7,  Yurii S Moroz 8 9,  John J Irwin 1,  Allan I Basbaum 10,  Bryan L Roth 11 12 13,  Brian K Shoichet 14
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA, 94158, USA.
  • 2 Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, 27514, USA.
  • 3 Department of Anatomy, University of California San Francisco, San Francisco, CA, 94158, USA.
  • 4 Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea.
  • 5 Center of Clinical Pharmacology, Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, 63110, USA.
  • 6 Enamine Ltd., Kyiv, Ukraine.
  • 7 V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences of Ukraine, Kyiv, Ukraine.
  • 8 Chemspace LLC, Kyiv, Ukraine.
  • 9 National Taras Shevchenko University of Kyiv, Kyiv, Ukraine.
  • 10 Department of Anatomy, University of California San Francisco, San Francisco, CA, 94158, USA. [email protected].
  • 11 Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, 27514, USA. [email protected].
  • 12 National Institute of Mental Health Psychoactive Drug Screening Program, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, 27514, USA. [email protected].
  • 13 Division of Chemical Biology and Medicinal Chemistry, University of North Carolina at Chapel Hill Eshelman School of Pharmacy, Chapel Hill, NC, 27514, USA. [email protected].
  • 14 Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA, 94158, USA. [email protected].
  • # Contributed equally.
PMID: 38057319 DOI: 10.1038/s41467-023-43506-6
Abstract

The lipid prostaglandin E2 (PGE2) mediates inflammatory pain by activating G protein-coupled receptors, including the prostaglandin E2 receptor 4 (EP4R). Nonsteroidal anti-inflammatory drugs (NSAIDs) reduce nociception by inhibiting prostaglandin synthesis, however, the disruption of upstream prostanoid biosynthesis can lead to pleiotropic effects including gastrointestinal bleeding and cardiac complications. In contrast, by acting downstream, EP4R antagonists may act specifically as anti-inflammatory agents and, to date, no selective EP4R antagonists have been approved for human use. In this work, seeking to diversify EP4R antagonist scaffolds, we computationally DOCK over 400 million compounds against an EP4R crystal structure and experimentally validate 71 highly ranked, de novo synthesized molecules. Further, we show how structure-based optimization of initial docking hits identifies a potent and selective antagonist with 16 nanomolar potency. Finally, we demonstrate favorable pharmacokinetics for the discovered compound as well as anti-allodynic and anti-inflammatory activity in several preclinical pain models in mice.

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