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

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.