Understanding human 15-hydroxyprostaglandin dehydrogenase binding with NAD⁺ and PGE₂ by homology modeling, docking and molecular dynamics simulation

Homology modeling, molecular docking, and molecular dynamics simulation have been performed to determine human 15-hydroxyprostaglandin dehydrogenase (15-PGDH) binding with its NAD⁺ cofactor and prostaglandin E2 (PGE₂) substrate. The computational studies have led to a three-dimensional (3D) model of the entire 15-PGDH-NAD⁺-PGE ₂ complex, demonstrating the detailed binding of PGE₂ with 15-PGDH for the first time. This 3D model shows specific interactions of the protein with the cofactor and substrate in qualitative agreement with available experimental data. Our model demonstrates the PGE₂-binding cavity of the protein for the first time. The model further leads to an interesting prediction that the catalytic activity of 15-PGDH should also significantly be affected by Gln148, in addition to the previously known three catalytic residues (Ser138, Tyr151, and Lys155). The reported 3D model of 15-PGDH-NAD ⁺-PGE₂ complex might be valuable for future rational design of novel inhibitors of 15-PGDH.