9PFL

Crystal structure of human 15-PGDH in complex with small molecule compound 1

This is a non-PDB format compatible entry.

Summary for 9PFL

• Entry DOI: 10.2210/pdb9pfl/pdb
• Descriptor: 15-hydroxyprostaglandin dehydrogenase [NAD(+)], (4S)-7-[7-(4,4-difluoropiperidine-1-carbonyl)-2,3-dihydro-4H-1,4-benzoxazin-4-yl]-2-methyl[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one, NICOTINAMIDE-ADENINE-DINUCLEOTIDE, ... (7 entities in total)
• Functional Keywords: small molecule inhibitor, 15-pgdh, prostaglandins e2, oxidoreductase, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 59966.59

Authors

Shaik, M.M.,Brennan, D. (deposition date: 2025-07-05, release date: 2025-09-10, Last modification date: 2025-09-17)

Primary citation

Dodda, L.S.,Campos, S.,Ciccone, D.,Carreiro, S.,Leit, S.,Brennan, D.,Zephyr, J.,Jacques-O'Hagan, S.,Kumar, S.,Kuo, F.S.,Shaik, M.M.,Price, D.J.,Loh, C.,Edmondson, S.D.,Tummino, P.,Kaila, N.
Knowledge and Structure-Based Drug Design of 15-PGDH Inhibitors.
J.Med.Chem., 68:18436-18462, 2025

PubMed 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.

PubMed: 40864846
DOI: 10.1021/acs.jmedchem.5c01231

Experimental method

X-RAY DIFFRACTION (1.65 Å)