Virtual screening, molecular docking, molecular dynamics and quantum chemical studies on (2-methoxy-4-prop-2-enylphenyl) N-(2-methoxy-4-nitrophenyl) carbamate: a novel inhibitor of hepatocellular carcinoma

HDAC protein is associated with hepatocellular carcinoma. Different medicinal plants were selected for this study to analyze the inhibitory efficacy against the target protein, HDAC. Using virtual screening, we filtered out the best compounds, and molecular docking (XP) was carried out for the top compounds which filtered out. The molecular docking results showed that the title compound (2-methoxy-4-prop-2-enylphenyl) N-(2-methoxy-4-nitrophenyl) carbamate (MEMNC) has the highest docking score of about −7.7 kcal/mol against the targeted protein histone deacetylase (HDAC) compared with the other selected phytocompounds. From the molecular dynamics analysis, the RMSD and RMSF plots depicted the overall stability of the protein–ligand complex. Toxicity properties show the acceptable range of various kinds of toxicity that were predicted using the ProTox-II server. In addition, DFT quantum chemical and physicochemical properties of the MEMNC molecule were reported. Initially, the molecular structure of the MEMNC molecule was optimized and harmonic vibrational frequencies were calculated using DFT/B3LYP method with a cc-pVTZ basis set using Gaussian 09 program. The calculated vibrational wavenumber values were assigned based on Potential Energy Distribution calculations using the VEDA 4.0 program and correlated well with the previous literature values. The molecule has bioactivity as a result of intramolecular charge transfer interactions, as demonstrated by frontier molecular orbital analysis. Molecular electrostatic potential surface and Mulliken atomic charge distribution analyses validate the reactive sites of the molecule. Thus, the title compound can be used as a potential inhibitor of HDAC protein, which paves the way for designing novel drugs to treat Hepatocellular carcinoma. Communicated by Ramaswamy H. Sarma组蛋白去乙酰化酶（histone deacetylase, HDAC）与肝细胞癌（hepatocellular carcinoma）密切相关。本研究选取多种药用植物，以分析其对靶蛋白HDAC的抑制效能。通过虚拟筛选（virtual screening），我们筛选得到最优化合物，并对筛选出的顶级化合物开展分子对接（XP）实验。分子对接结果显示，标题化合物(2-甲氧基-4-丙-2-烯基苯基) N-(2-甲氧基-4-硝基苯基)氨基甲酸酯（MEMNC）相较于其他所选植物源化合物，对靶蛋白HDAC的对接得分最高，约为-7.7 kcal/mol。分子动力学分析中，均方根偏差（Root Mean Square Deviation, RMSD）与均方根波动（Root Mean Square Fluctuation, RMSF）图谱展现了蛋白-配体复合物的整体稳定性。毒性性质分析表明，通过ProTox-II服务器预测的各类毒性均处于可接受范围。此外，本研究还报道了MEMNC分子的密度泛函理论（Density Functional Theory, DFT）量子化学性质与理化性质。首先，我们采用Gaussian 09程序，以DFT/B3LYP方法结合cc-pVTZ基组，对MEMNC分子的结构进行优化，并计算其简谐振动频率。基于势能分布（Potential Energy Distribution）计算，通过VEDA 4.0程序对计算得到的振动波数进行归属，且该结果与既往文献报道值吻合良好。前沿分子轨道分析证实，分子内电荷转移相互作用赋予该分子生物活性。分子静电势表面与马利肯（Mulliken）原子电荷分布分析验证了该分子的反应活性位点。综上，该标题化合物可作为HDAC蛋白的潜在抑制剂，为开发治疗肝细胞癌的新型药物奠定了研究基础。本文由Ramaswamy H. Sarma供稿。