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

Area of Science:

• Biochemistry
• Pharmacology
• Computational Chemistry

Background:

• Prostaglandin E2 (PGE2) is crucial for immune cell function and tissue regeneration.
• 15-prostaglandin dehydrogenase (15-PGDH) inactivates PGE2, making its inhibition a therapeutic target.

Purpose of the Study:

• To solve the first cocrystal structure of 15-PGDH with small molecule inhibitors.
• To rationally design novel 15-PGDH inhibitors using structure-based approaches and computational tools.
• To validate the therapeutic hypothesis of elevating PGE2 levels through 15-PGDH inhibition.

Main Methods:

• Cocrystallization of 15-PGDH with small molecule inhibitors.
• Structure-based drug design.
• Advanced computational methods including Free Energy Perturbation (FEP+) and WaterMap.
• Machine learning (ML) model development for guiding synthetic priorities.
• In vivo administration (IP) in mice to measure colonic PGE2 levels.

Main Results:

• The first cocrystal structure of 15-PGDH bound to inhibitors was determined.
• Novel series of 15-PGDH inhibitors were developed through rational design and computational modeling.
• A machine learning model effectively guided the prioritization of synthetic compounds.
• A lead compound successfully elevated colonic PGE2 levels in mice after administration.

Conclusions:

• Structure-based design and computational methods are effective for developing potent 15-PGDH inhibitors.
• Inhibiting 15-PGDH is a viable strategy for increasing PGE2 levels.
• The developed compounds hold therapeutic potential for conditions benefiting from enhanced PGE2 signaling.