Rampogu Shailima, Ravinder Doneti, Pawar Smita C, Lee Keun Woo
Division of Life Science, Division of Applied Life Science (BK21 Plus), Plant Molecular Biology and Biotechnology Research Center (PMBBRC), Research Institute of Natural Science (RINS), Gyeongsang National University (GNU), 501 Jinju-daero, Jinju 52828, Korea.
Department of Genetics, University College of Science, Osmania University, Hyderabad 500 007, Telangana, India.
J Clin Med. 2018 Dec 15;7(12):551. doi: 10.3390/jcm7120551.
Cervical cancer is regarded as one of the major burdens noticed in women next to breast cancer. Although, human papilloma viruses (HPVs) are regarded as the principal causative agents, they require certain other factors such as oestrogen hormone to induce cervical cancer. Aromatase is an enzyme that converts androgens into oestrogens and hindering this enzyme could subsequently hamper the formation of oestrogen thereby alleviating the disease. Accordingly, in the current investigation, a structure based pharmacophore was generated considering two proteins bearing the Protein Data Bank (PDB) codes 3EQM (pharm 1) and 3S7S (pharm 2), respectively. The two models were employed as the 3D query to screen the in-house built natural compounds database. The obtained 51 compounds were escalated to molecular docking studies to decipher on the binding affinities and to predict the quintessential binding modes which were affirmed by molecular dynamics (MD) simulations. The compound has induced dose-dependent down regulation of PP2B, Nitric oxide synthase-2 (NOS2), and Interleukin 6 (IL-6) genes in the HeLa cells and has modulated the expression of apoptotic genes such as Bax, Bcl2, and caspases-3 at different concentrations. These results guide us to comprehend that the identified aromatase inhibitor was effective against the cervical cancer cells and additionally could server as scaffolds in designing new drugs.
宫颈癌被视为仅次于乳腺癌的女性主要负担之一。虽然人乳头瘤病毒（HPV）被认为是主要致病因素，但它们还需要某些其他因素，如雌激素，才能诱发宫颈癌。芳香化酶是一种将雄激素转化为雌激素的酶，抑制这种酶可能会阻碍雌激素的形成，从而缓解疾病。因此，在当前的研究中，基于结构的药效团是根据分别具有蛋白质数据库（PDB）代码3EQM（药效团1）和3S7S（药效团2）的两种蛋白质生成的。这两个模型被用作3D查询，以筛选内部构建的天然化合物数据库。所获得的51种化合物被升级到分子对接研究，以解读结合亲和力并预测典型的结合模式，这些模式通过分子动力学（MD）模拟得到了证实。该化合物在HeLa细胞中诱导了PP2B、一氧化氮合酶2（NOS2）和白细胞介素6（IL-6）基因的剂量依赖性下调，并在不同浓度下调节了凋亡基因如Bax、Bcl2和半胱天冬酶-3的表达。这些结果使我们认识到，所鉴定的芳香化酶抑制剂对宫颈癌细胞有效，并且还可以作为设计新药的支架。
