Docking for EP4R antagonists active against inflammatory pain

Stefan Gahbauer, Chelsea DeLeon, Joao M. Braz, Veronica Craik, Hye Jin Kang, Xiaobo Wan, Xi-Ping Huang, Christian B. Billesbølle, Yongfeng Liu, Tao Che, Ishan Deshpande, Madison Jewell, Elissa A. Fink, Ivan S. Kondratov, Yurii S. Moroz, John J. Irwin, Allan I. Basbaum (), Bryan L. Roth () and Brian K. Shoichet ()
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Stefan Gahbauer: University of California San Francisco
Chelsea DeLeon: University of North Carolina at Chapel Hill School of Medicine
Joao M. Braz: University of California San Francisco
Veronica Craik: University of California San Francisco
Hye Jin Kang: University of North Carolina at Chapel Hill School of Medicine
Xiaobo Wan: University of California San Francisco
Xi-Ping Huang: University of North Carolina at Chapel Hill School of Medicine
Christian B. Billesbølle: University of California San Francisco
Yongfeng Liu: University of North Carolina at Chapel Hill School of Medicine
Tao Che: University of North Carolina at Chapel Hill School of Medicine
Ishan Deshpande: University of California San Francisco
Madison Jewell: University of California San Francisco
Elissa A. Fink: University of California San Francisco
Ivan S. Kondratov: Enamine Ltd.
Yurii S. Moroz: Chemspace LLC
John J. Irwin: University of California San Francisco
Allan I. Basbaum: University of California San Francisco
Bryan L. Roth: University of North Carolina at Chapel Hill School of Medicine
Brian K. Shoichet: University of California San Francisco

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-43506-6

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