2. Academic Validation
  3. Knowledge and Structure-Based Drug Design of 15-PGDH Inhibitors

Knowledge and Structure-Based Drug Design of 15-PGDH Inhibitors

  • J Med Chem. 2025 Sep 11;68(17):18436-18462. doi: 10.1021/acs.jmedchem.5c01231.
Leela S Dodda 1,  Sebastien Campos 2,  David Ciccone 1,  Samantha Carreiro 1,  Silvana Leit 1,  Debra Brennan 1,  Jacqueto Zephyr 1,  Suzanne Jacques-O'Hagan 1,  Sheetal Kumar 1,  Fu-Shan Kuo 1,  Md Munan Shaik 1,  Daniel J Price 1,  Christine Loh 1,  Scott D Edmondson 1,  Peter Tummino 1,  Neelu Kaila 1
Affiliations

Affiliations

  • 1 Nimbus Therapeutics, Boston, Massachusetts 02210, United States.
  • 2 Pharmaron, Hoddesdon EN119FH, U.K.
PMID: 40864846 DOI: 10.1021/acs.jmedchem.5c01231
Abstract

PGE2 plays important roles in immune cell function and in potentiating tissue regeneration. 15-PGDH is the key enzyme involved in inactivation of PGE2 and its inhibition therefore provides valuable therapeutic opportunity. We have solved the first cocrystal structure of 15-PGDH bound to small molecule inhibitors, enabling us to efficiently investigate and understand the key functionalities required for potency. Rational structure-based design coupled with a host of advanced computational methods, including FEP+ and WaterMap, were used to develop novel series of 15-PGDH inhibitors. Of note, a machine-learning (ML) model trained with potencies predicted by FEP+ yielded a powerful tool to guide synthetic priority across a large virtual chemical library. Ultimately, a lead compound demonstrated elevation of colonic PGE2 following IP administration in mice, consistent with our therapeutic hypothesis.

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