Plant derived anti-cancerous secondary metabolites as multipronged inhibitor of COX, Topo, and aromatase: molecular modeling and dynamics simulation analyses
Plant derived anti-cancerous secondary metabolites as multipronged inhibitor of COX, Topo, and aromatase: molecular modeling and dynamics simulation analyses
复制标题
DOI：
10.1080/07391102.2016.1241720
复制
发表时间：
2017-10
影响因子：
4.4
通讯作者：
Swati Singh;Manika Awasthi;V. P. Pandey;U. Dwivedi
中科院分区：
文献类型：
--
作者：
Swati Singh;Manika Awasthi;V. P. Pandey;U. Dwivedi
在本研究中，300植物衍生的次生代谢产物（生物碱，类黄酮和萜类化合物各100），已筛选其抗癌活性，通过抑制选定的关键酶的目标，即环氧合酶（COX），拓扑异构酶（Topos），芳香化酶的分子对接方法。此外，使用分子动力学（MD）模拟分析和结合自由能计算分析了来自每类次级代谢产物的顶部命中物与其各自酶靶的复合物的稳定性。根据药物动力学筛选的18种生物碱，26种黄酮类化合物和9种萜类化合物的对接结果的分析表明，黄酮类化合物姜黄素是所有选定的酶靶点的最有效的抑制剂。还通过MD模拟分析分析了考克斯-1、考克斯-2、Topo I、Topo IIβ和芳香酶与最有效的抑制剂姜黄素和相应药物（即布洛芬、阿司匹林、拓扑替康、依托泊苷和阿司美坦）的复合物的稳定性，其显示姜黄素复合物的稳定性优于相应药物的稳定性。姜黄素与所有目标的复合物的结合能计算，除了Topos的那些，表现出较低的结合能的姜黄素复合物比那些相应的药物，这证实了与分子对接分析的结果。因此，本研究肯定了姜黄素的多功能和多管齐下的性质，传统上使用的草药，作为抗癌分子针对这些酶的目标。
In the present study, 300 plant derived secondary metabolites (100 each of alkaloid, flavonoid, and terpenoid), have been screened for their anti-cancerous activity through inhibition of selected key enzymatic targets, namely cyclooxygenases (COXs), topoisomerases (Topos), and aromatase by molecular docking approach. Furthermore, the stability of the complexes of top hits, from each class of secondary metabolites, with their respective enzymatic targets was analyzed using molecular dynamics (MD) simulation analyses and binding free energy calculations. Analysis of the results of the docking in light of the pharmacokinetically screened 18 alkaloids, 26 flavonoids, and 9 terpenoids, revealed that the flavonoid, curcumin, was the most potent inhibitor for all the selected enzymatic targets. The stability of the complexes of COX-1, COX-2, Topo I, Topo IIβ and aromatase with the most potent inhibitor curcumin and those of the respective drugs, namely ibuprofen, aspirin, topotecan, etoposide, and exemestane were also analyzed through MD simulation analyses which revealed better stability of curcumin complexes than those of respective drugs. Binding energy calculations of the complexes of the curcumin with all the targets, except those of Topos, exhibited lower binding energies for the curcumin complexes than those of respective drugs which corroborated with the results of molecular docking analyses. Thus, the present study affirms the versatile and multipronged nature of curcumin, the traditionally used herbal medicine, as anti-cancer molecule directed against these enzymatic targets.