Dipeptidyl peptidase-IV enzyme is one of the targets for drug design to compact type-2 diabetes. The current research addresses the design, modeling, synthesis and in vitro testing of potential new DPP-IV inhibitors. X-ray structure of Sitagliptin with DPP-IV indicated hydrophobic interaction of the triazolo-piperazine ring system with the S2 pocket through the amino acid Phe357. Using molecular modeling; we designed new compounds with better hydrophobic properties facing Phe357. Six compounds were designed, docked, synthesized and tested for DPP-IV inhibitory activity.

All designed compounds showed comparable affinity to the catalytic site of the enzyme to that of the standard drug, however, the activity as inhibitors, as reflected by the IC50 range of 0.3 μM – 1.3 μM, was lower than that of Sitagliptin (IC50 22 nM). The most active compound in the new series with, IC50 of 0.3 μM, showed interesting a flipped over docking mode that is different from all other compounds including Sitagliptin with the lipophilic area directed away from the amino acid Phe357. The forces of interaction of the most active compound with the enzyme catalytic site were determined from modeling studies, binding can be optimized by further structural modifications.

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