Abdjan Muhammad Ikhlas, Aminah Nanik Siti, Siswanto Imam, Kristanti Alfinda Novi, Takaya Yoshiaki, Choudhary Muhammad Iqbal
Departement of Chemistry, Faculty of Science and Technology, Universitas Airlangga Surabaya 60115 Indonesia
Biotechnology of Tropical Medicinal Plants Research Group, Universitas Airlangga Indonesia.
RSC Adv. 2021 May 27;11(31):19323-19332. doi: 10.1039/d1ra02233d. eCollection 2021 May 24.
A combination of molecular docking and molecular dynamics simulation (250 ns) has been carried out to study the interaction of stilbenoid trimer compounds with the SIRT1 enzyme as the target protein. SIRT1 expression regulates cellular stress responses that lead to the development of cancer. Redocking showed a good native ligand pose with an RMSD value of 1.40 Å at the receptor active site's coordinates. The molecular docking score uses a grid score functional (kcal mol), which shows results of 1NS: 79.56, TS1: -26.83, TS2: -87.77, and TS3: -83.67. The TS2 and TS3 candidates were chosen for further analysis because they had a lower grid score than the native ligand (1NS). Furthermore, prediction of binding free energy (kcal mol) using the Quantum Mechanics/generalized Born Surface Area (QM/MM-GBSA) method shows the results of 1NS: -31.52 ± 0.39, TS2: -58.99 ± 0.34, and TS3: -43.38 ± 0.35. These results indicate that the TS2 and TS3 compounds have good potential as inhibitors of the SIRT1 enzyme. Additionally, the amino acid residues were responsible for the inhibition mechanism through hydrogen bond interactions at the molecular level, including ASP22, PHE91, PRO11, ILE165, ASP166, and VAL230. The observations made in this study provide theoretical information for exploring the stilbenoid trimers as anticancer agents by targeting the SIRT1 enzyme.
已进行分子对接和分子动力学模拟（250纳秒）相结合的研究，以探究芪类三聚体化合物与作为靶蛋白的SIRT1酶之间的相互作用。SIRT1的表达调节导致癌症发生的细胞应激反应。重新对接显示在受体活性位点坐标处，天然配体构象良好，均方根偏差（RMSD）值为1.40 Å。分子对接分数使用网格分数函数（千卡/摩尔），结果显示1NS为79.56，TS1为 -26.83，TS2为 -87.77，TS3为 -83.67。选择TS2和TS3候选物进行进一步分析，因为它们的网格分数低于天然配体（1NS）。此外，使用量子力学/广义玻恩表面积（QM/MM - GBSA）方法预测的结合自由能（千卡/摩尔）结果显示，1NS为 -31.52±0.39，TS2为 -58.99±0.34，TS3为 -43.38±0.35。这些结果表明，TS2和TS3化合物作为SIRT1酶抑制剂具有良好的潜力。此外，氨基酸残基通过分子水平的氢键相互作用负责抑制机制，包括ASP22、PHE91、PRO11、ILE165、ASP166和VAL230。本研究中的观察结果为通过靶向SIRT1酶探索芪类三聚体作为抗癌剂提供了理论信息。
