PDF(Pubmed)
Abstract：
DPP4 inhibitors can control glucose homeostasis by increasing the level of GLP-1 incretins hormone due to dipeptidase mimicking. Despite the potent effects of DPP4 inhibitors, these compounds cause unwanted toxicity attributable to their effect on other enzymes. As a result, it seems essential to find novel and DPP4 selective compounds. In this study, we introduce a potent and selective DPP4 inhibitor via structure-based virtual screening, molecular docking, molecular dynamics simulation, MM/PBSA calculations, DFT analysis, and ADMET profile. The screened compounds based on similarity with FDA-approved DPP4 inhibitors were docked towards the DPP4 enzyme. The compound with the highest docking score, ZINC000003015356, was selected. For further considerations, molecular docking studies were performed on selected ligands and FDA-approved drugs for DPP8 and DPP9 enzymes. Molecular dynamics simulation was run during 200 ns and the analysis of RMSD, RMSF, Rg, PCA, and hydrogen bonding were performed. The MD outputs showed stability of the ligand-protein complex compared to available drugs in the market. The total free binding energy obtained for the proposed DPP4 inhibitor was more negative than its co-crystal ligand (N7F). ZINC000003015356 confirmed the role of the five Lipinski rule and also, have low toxicity parameter according to properties. Finally, DFT calculations indicated that this compound is sufficiently soft.
摘要：
DPP4抑制剂可以通过增加由于二肽酶模拟的GLP-1肠促胰岛素激素水平来控制葡萄糖稳态。尽管DPP4抑制剂的有效作用，这些化合物由于它们对其他酶的影响而引起不希望的毒性。因此,寻找新的DPP4选择性化合物似乎是必不可少的。在这项研究中,我们通过基于结构的虚拟筛选引入了一种有效和选择性的DPP4抑制剂，分子对接,分子动力学模拟,MM/PBSA计算，DFT分析,和ADMET配置文件。将基于与FDA批准的DPP4抑制剂的相似性的筛选化合物与DPP4酶对接。对接得分最高的化合物，选择ZINC000003015356。为了进一步考虑，对选定的配体和FDA批准的DPP8和DPP9酶药物进行了分子对接研究。分子动力学模拟在200ns内运行，RMSD分析，RMSF,Rg,PCA,和氢键。MD输出显示与市场上可获得的药物相比,配体-蛋白质复合物的稳定性。所提出的DPP4抑制剂获得的总自由结合能比其共晶配体(N7F)更负。ZINC000003015356确认了五个Lipinski规则的作用，根据性质具有低毒性参数。最后,DFT计算表明该化合物足够软。
