Discovery of the selective and nanomolar inhibitor of DPP-4 more potent than sitagliptin by structure-guided rational design

Various therapeutic targets and approaches are commonly employed in the management of Type 2 Diabetes. These encompass diverse groups of drugs that target different mechanisms involved in glucose regulation. Inhibition of the DPP-4 enzyme has been proven an excellent target for antidiabetic drug design. Our previous work on discovering multitarget antidiabetic drugs led to the identification of a gallic acid-thiazolidinedione hybrid as a potent DPP4 inhibitor (IC₅₀ = 36 nM). In current research, our efforts resulted in a new dihydropyrimidine-based scaffold with enhanced DPP4 inhibition potential. After virtual evaluation, the designed molecules with excellent interaction patterns and binding energy values were synthesized in the wet laboratory. The inhibition potential of synthesized compounds was assessed against the DPP-4 enzyme. Compound 46 with single digit IC₅₀ value 2 nM exhibited 4-fold and 18-fold higher activity than Sitagliptin and our previously reported hybrid respectively. Moreover, compounds 46, 47 and 50 have shown manyfold selectivity against DPP8 and DPP9. Further pretreatment with compounds 43, 45–47 and 50 (at doses of 10 and 20 mg/kg) in OGTT conducted on rats resulted in a significant decrease in the serum glucose levels compared to the control group. In the long-term STZ-induced diabetic rats, tested compound 50 performed similarly to the reference drug. Molecular dynamics simulations and in-silico molecular docking studies were employed to elucidate the time-dependent interactions of inhibitors within the active sites of DPP4. The compounds examined in this work might serve as a possible lead in the development of effective diabetic mellitus treatments.