Background: Dipeptidyl peptidase IV has been reported to be an important target for the development and discovery of new therapies for diabetes mellitus type II.

Objective: The main aim of this study was to discover chemical entities that target the inhibition of DPP IV and feature potent hypoglycemic action.

Methods: A structure-based virtual screening was applied to discover new hypoglycemic agents. Molecular docking was performed to compute the binding free energies. Molecular dynamics simulations were done to evaluate the binding stability of resulted hits.

Results: Seven small non-peptide potential inhibitors of Dipeptidyl peptidase IV with 3-imino-4-(4- substituted phenyl)-1, 2, 5-thiadiazolidine-1,1-dioxide scaffold were discovered. The binding free energies ranged from -24.50 to -36.06 kJ/mol. Molecular dynamics simulations revealed high stability of all protein-ligand complexes with low root mean square deviation over 10 ns simulation time. The tested compounds expressed a significant reduction in blood glucose level up to 90% with excellent oral glucose tolerance test after 120 minutes of injection in a diabetes mellitus type II animal model. A promising release of insulin was observed with a potential hypoglycemic activity for all compounds.

Conclusion: The virtual screening was successful to discover potent hypoglycemic agents with drug-like properties that may need more consideration for future studies and development.

背景：据报道，二肽基肽酶 IV 是开发和发现 II 型糖尿病新疗法的重要靶点。

目的：本研究的主要目的是发现靶向抑制 DPP IV 并具有有效降血糖作用的化学实体。

方法：应用基于结构的虚拟筛选来发现新的降血糖药。进行分子对接以计算结合自由能。进行分子动力学模拟以评估结果命中的结合稳定性。

结果：发现了七种具有 3-亚氨基-4-(4-取代苯基)-1, 2, 5-噻二唑烷-1,1-二氧化物支架的二肽基肽酶 IV 的小型非肽潜在抑制剂。结合自由能范围为-24.50 至-36.06 kJ/mol。分子动力学模拟显示所有蛋白质-配体复合物在 10 ns 模拟时间内均具有低均方根偏差的高稳定性。在 II 型糖尿病动物模型中注射 120 分钟后，经测试的化合物表现出血糖水平显着降低高达 90%，具有出色的口服葡萄糖耐量试验。观察到有希望的胰岛素释放，所有化合物都具有潜在的降血糖活性。

结论：虚拟筛选成功地发现了具有类似药物特性的强效降糖药，可能需要在未来的研究和开发中更多地考虑。