Covalent Inhibition Mechanism of Antidiabetic Drugs-Vildagliptin vs Saxagliptin
Covalent Inhibition Mechanism of Antidiabetic Drugs-Vildagliptin vs Saxagliptin
复制标题
抗糖尿病药物的共价抑制机制-维格列汀 vs 沙格列汀
DOI：
10.1021/acscatal.8b05051
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发表时间：
2019-03-01
期刊：
影响因子：
12.9
通讯作者：
Wu, Ruibo
中科院分区：
文献类型：
--
作者：
Wang, Yong-Heng;Zhang, Fan;Wu, Ruibo
维格列汀（VIL）和沙格列汀（SAX）是治疗2型糖尿病的两种共价药物。已知VIL和SAX的主要药理作用源于它们在二肽基肽酶-4 （DPP-4）活性位点的生化反应，DPP-4是一种丝氨酸蛋白酶，可迅速灭活血浆中的肠促胰岛素激素。然而，两种支架相似药物的催化机制和不同药代动力学行为的起源细节尚不清楚。通过量子力学/分子力学分子动力学模拟，揭示了DPP-4的催化过程包括两个主要步骤：可逆共价键对抗糖尿病靶点DPP-4进行共价修饰和不可逆水解反应，将药物转化为无活性代谢产物。反应自由能谱表明，VIL主要通过水解途径与DPP-4解离，而SAX主要通过相反的共价键过程与DPP-4解离。因此，对VIL的抑制是假不可逆的，而对SAX的抑制是可逆的。进一步的比较研究表明，SAX中吡咯烷环的4,5-亚甲基取代基与VIL相比具有不同的解离动力学特征和更高的抑制活性。这些发现与前人报道的实验结果一致，对进一步设计DPP-4共价药物具有指导意义。
Vildagliptin (VIL) and saxagliptin (SAX) are two covalent drugs for the treatment of type 2 diabetes mellitus. The principal pharmacological effects of VIL and SAX are known to arise from their biochemical reactions at the active site of dipeptidyl peptidase-4 (DPP-4), a serine protease that rapidly inactivates incretin hormones in plasma. However, the details of the catalytic mechanisms and the origin of the different pharmacokinetics behavior for the two scaffold-similar drugs are less clear. By employing quantum mechanical/molecular mechanical molecular dynamics simulations in this work, it is illuminated that the catalytic process involves two major steps: reversible covalent bonding which covalently modifies the antidiabetic target DPP-4 and irreversible hydrolysis reaction which converts the drugs into inactive metabolites. The reaction free energy profiles indicate that VIL is dissociated from DPP-4 mainly through the hydrolysis pathway, while SAX overwhelmingly through the reverse process of covalent bonding. Therefore, the inhibition is pseudoirreversible for VIL, while reversible for SAX. Further comparative studies reveal that the 4,5-methylene substituent of pyrrolidine ring in SAX is responsible for the different dissociation kinetics features and its higher inhibitory activity compared to the VIL. All these findings are in agreement with the previously reported experimental results and guidable for further covalent drug design toward DPP-4.