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.