发现新型抗癌类黄酮作为潜在的 HDAC2 抑制剂：基于分子对接的虚拟筛选方法，DFT 和分子动力学模拟研究。Discovery of novel anticancer flavonoids as potential HDAC2 inhibitors: virtual screening approach based on molecular docking, DFT and molecular dynamics simulations studies.-医云文献数字医云科研云海量医学决策数据服务

Abstract：

Virtual screening of a library of 329 flavonoids obtained from the NPACT database was performed to find out potential novel HDAC2 inhibitors. Eleven out of 329 selected flavonoids were screened based on molecular docking studies, as they have higher binding affinities than the standard drugs vorinostat and panobinostat. All screened compounds occupying the catalytic site of HDAC2 showed important molecular interaction with Zn2+ and other important amino acids in the binding pocket. The screened compounds were validated using ADMET filtration and bioactivity prediction from which we obtained six compounds, NPACT00270, NPACT00676, NPACT00700, NPACT001008, NPACT001054, and NPACT001407, which were analyzed using DFT studies. DFT studies were performed for all six screened flavonoids. In DFT studies, three flavonoids, NPACT00700, NPACT001008, and NPACT001407, were found to be better based on HOMO-LUMO and molecular electrostatic potential (MEP) analyses. Furthermore, MD simulations were performed for 100 ns for the three compounds. In the MD analysis, NPACT001407 was found to be more stable in the active site of HDAC2 as zinc formed a coordination bond with ASP181, HIS183, ASP269, and GLY305, along with two hydroxyl groups of the ligand. Our findings reveal that these flavonoids can interact as ligands with the active site of HDAC2. Because of the absence of a hydroxamate group in flavonoids, there are no possibilities for the formation of isocyanate. This suggests that the major drawback of current HDACs inhibitors may be solved. Further experimental validation is needed to understand the selectivity of flavonoids as HDAC2 inhibitors.
UNASSIGNED: The online version contains supplementary material available at 10.1007/s13205-023-03912-5.

摘要：

对从NPACT数据库获得的329类黄酮文库进行虚拟筛选以发现潜在的新型HDAC2抑制剂。根据分子对接研究筛选出329种黄酮类化合物中的11种，因为它们比标准药物伏立诺他和帕比司他具有更高的结合亲和力。所有筛选的占据HDAC2催化位点的化合物均显示出与结合袋中的Zn2和其他重要氨基酸的重要分子相互作用。使用ADMET过滤和生物活性预测对筛选的化合物进行了验证，从中我们获得了六个化合物，NPACT00270、NPACT00676、NPACT00700、NPACT001008、NPACT001054和NPACT001407使用DFT研究进行分析。对所有六种筛选的类黄酮进行DFT研究。在DFT研究中，三种类黄酮，根据HOMO-LUMO和分子静电势（MEP）分析，发现NPACT00700，NPACT001008和NPACT001407更好。此外，对三种化合物进行了100纳秒的MD模拟。在MD分析中，发现NPACT001407在HDAC2的活性位点中更稳定，因为锌与ASP181，HIS183，ASP269和GLY305以及配体的两个羟基形成配位键。我们的发现表明，这些类黄酮可以作为配体与HDAC2的活性位点相互作用。因为类黄酮中没有异羟肟基,不可能形成异氰酸酯。这表明可以解决当前HDAC抑制剂的主要缺点。需要进一步的实验验证来了解类黄酮作为HDAC2抑制剂的选择性。
■在线版本包含补充材料，可在10.1007/s13205-023-03912-5获得。