CYTOTOXIC ACTIVITY AND MOLECULAR DOCKING STUDY OF 4- SUBSTITUTED FLAVYLIUM SALT

D. Milenkovic, M. Zivanovic, M. Dekić, Marijana Stanojević Pirković, Jelena R. Đorović Jovanović
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Abstract

In the present manuscript, the cytotoxic activity of flavylium cation substituted at 4- position with phenyl (FC-4Ph) was tested to two cells lines (human colorectal carcinoma, HCT-116, and human fibroblast lung, MRC-5). In vitro cytotoxicity experiments were performed to elucidate the possible anticancer activity of tested substance. Investigated compound did not show cytotoxic effect on HCT-116 after 24 h, while after 72 h exerted significant effect. A significant selectivity towards colorectal carcinoma cells was observed. On the other hand, this compound did not show any effect on MRC-5 cell line. The molecular interactions between receptor tyrosine kinase (RTK) and title compound was examined. The crystal structure of investigated receptor RTK was downloaded from Protein Data Bank. The native bound ligand ((E)-[4-(3,5-difluorophenyl)-3H-pyrrolo[2,3-b]pyridin-3-ylidene](3- methoxyphenyl)methanol was extracted from receptor and binding pocket analysis was performed. Re-docking was carried out with the FC-4Ph in order to generate the same docking pose as found in co-crystallized form of receptor. The obtained results of revealed that investigated compound binds at the same binding pockets to RTK, as well as native bound ligand, by weak non-covalent interactions. The most prominent interactions are hydrogen bonds, π-alkyl, and π-π interactions. The preliminary results suggest that investigated compound showed good binding affinity against RTK, as evident from the free binding energy (ΔGbind in kJ/mol).
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4-取代黄盐的细胞毒活性及分子对接研究
在本论文中,我们对两种细胞系(人结直肠癌HCT-116和人肺成纤维细胞MRC-5)进行了4位苯基取代黄离子(FC-4Ph)的细胞毒活性测试。体外细胞毒性实验研究了所试物质的抗肿瘤活性。24 h后化合物对HCT-116细胞毒作用不明显,72 h后作用显著。对结直肠癌细胞有明显的选择性。另一方面,该化合物对MRC-5细胞系没有任何影响。研究了受体酪氨酸激酶(RTK)与标题化合物之间的分子相互作用。所研究受体RTK的晶体结构从蛋白质数据库下载。从受体中提取天然结合配体((E)-[4-(3,5-二氟苯基)- 3h -吡咯[2,3-b]吡啶-3-乙基](3-甲氧基苯基)甲醇,并进行结合袋分析。与FC-4Ph进行重新对接,以产生与共结晶形式的受体相同的对接姿态。结果表明,所研究的化合物通过弱非共价相互作用与RTK以及天然结合配体在相同的结合口袋上结合。最突出的相互作用是氢键、π-烷基和π-π相互作用。初步结果表明,化合物对RTK具有良好的结合亲和力,其自由结合能为ΔGbind (kJ/mol)。
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