Using Molecular Docking to Develop Inhibitors of DPP‐IV Enzyme

Dipeptidyl peptidase‐IV enzyme is a relatively new target for type 2 diabetes. Sitagliptin is the first FDA approved inhibitor of this enzyme to be introduced to the market for clinical use. The binding mode of Sitagliptin in the crystal structure of DPP‐IV showed a key interaction between the triazolopiperazine moiety and Phe357 residue in the S2 pocket of the active site. With the aid of molecular modelling, we designed new compounds in which the triazolopiperazine ring system of Sitagliptin was replaced by more hydrophobic moieties to enhance the interaction with Phe357. Six compounds were designed, synthesized and tested for their activity against DPP‐IV. The compounds showed IC 50 values that range from 0.3μM‐ 1.3μM. The most active compound (IC 50 = 0.3μM) showed 3–4 folds higher activity than the rest of the compounds, and more interestingly showed a different docking mode from all other compounds. While the most active compound showed lower activity than Sitagliptin (IC 50 = 22nM), the modelling data obtained from the binding modes of those compounds sheds the light on possible structural modifications to optimize the affinity to the enzyme. More compounds are currently under design, some of which will be addressed to highlight the key interactions contributing to the affinity of DPP‐IV inhibitors to the active site. Support or Funding Information This research was funded by MCPHS UniversitySitagliptin in the active site of DPP‐IVThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .