密花美登木叶查尔酮对T47D乳腺癌细胞系的细胞毒性及其基于药效团-分子动力学模拟作为雌激素受体拮抗剂的预测
Cytotoxicity Of Chalcone Of Burm F. Leaves Against T47D Breast Cancer Cell Lines And Its Prediction As An Estrogen Receptor Antagonist Based On Pharmacophore-Molecular Dynamics Simulation.
作者信息
Muchtaridi Muchtaridi, Yusuf Muhammad, Syahidah Hasna Nur, Subarnas Anas, Zamri Adel, Bryant Sharon D, Langer Thierry
机构信息
Department of Pharmaceutical Analysis and Medicinal Chemistry, Faculty of Pharmacy, Universitas Padjadjaran, Bandung, West Java, Indonesia.
Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Padjadjaran, Bandung, West Java, Indonesia.
出版信息
Adv Appl Bioinform Chem. 2019 Nov 6;12:33-43. doi: 10.2147/AABC.S217205. eCollection 2019.
BACKGROUND
The 2',4'-dihydroxy-6-methoxy-3,5-3-dimethylchalcone (ChalcEA) isolated from Burm f. leaves has potential anticancer activity against human breast-adenocarcinoma cell lines (MCF-7) with an IC value of 250 µM. However, its apoptotic activity on the T47D breast cancer cell lines which is involving caspase-3 has not been investigated.
MATERIALS AND METHODS
Therefore, this study aims to evaluate the cytotoxicity of ChalcEA on the T47D cell lines using the 2-(4-iodophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium (WST) method and to predict its possible antagonistic activity on the human estrogen receptor alpha (hERα) using pharmacophore and molecular dynamics (MD) methods. The test of 10 synthesized ChalcEA derivatives was also performed as an insight into the further development of its structure as an anticancer agent.
RESULTS
It is shown that ChalcEA has an IC of 142.58 ± 4.6 µM against the hERα-overexpressed T47D breast cancer cell lines, indicating its possible mechanism of anticancer activity as an antagonist of hERα. Pharmacophore study showed that ChalcEA shares similar features with the known hERα antagonist, 4-hydroxytamoxifen (4-OHT), which has hydrogen bond donor (HBD), hydrogen bond acceptor (HBA), ring aromaticity (RA), and hydrophobicity (Hy) features. Molecular docking showed that ChalcEA formed hydrogen bonds with Glu353 and Arg394, and hydrophobic interactions in a similar manner with 4-OHT. Moreover, MD simulations showed that ChalcEA destabilized the conformation of His524, a remarkable behavior of a known hERa antagonist, including 4-OHT. Furthermore, the 10 best chalcone derivatives resulted from pharmacophore- and docking-based screening, were tested against the T47D cell lines. None of the derivatives have better activity than ChalcEA. It is suggested that the functional groups at the B-ring of ChalcEA are interesting to be further optimized in the next studies.
CONCLUSION
ChalcEA might act as an antagonist toward hERα, thus warranting further investigation as a potential anticancer agent.
背景
从缅甸叶中分离出的2',4'-二羟基-6-甲氧基-3,5-二甲基查耳酮（ChalcEA）对人乳腺癌细胞系（MCF-7）具有潜在的抗癌活性，IC值为250μM。然而，其对涉及半胱天冬酶-3的T47D乳腺癌细胞系的凋亡活性尚未得到研究。
材料与方法
因此，本研究旨在使用2-(4-碘苯基)-3-(4-硝基苯基)-5-(2,4-二磺酸苯基)-2H-四唑鎓（WST）方法评估ChalcEA对T47D细胞系的细胞毒性，并使用药效团和分子动力学（MD）方法预测其对人雌激素受体α（hERα）的可能拮抗活性。还对10种合成的ChalcEA衍生物进行了测试，以深入了解其作为抗癌剂的结构进一步开发。
结果
结果表明，ChalcEA对hERα过表达的T47D乳腺癌细胞系的IC值为142.58±4.6μM，表明其作为hERα拮抗剂可能的抗癌活性机制。药效团研究表明，ChalcEA与已知的hERα拮抗剂4-羟基他莫昔芬（4-OHT）具有相似的特征，具有氢键供体（HBD）、氢键受体（HBA）、环芳香性（RA）和疏水性（Hy）特征。分子对接表明，ChalcEA与Glu353和Arg394形成氢键，并以与4-OHT相似的方式形成疏水相互作用。此外，MD模拟表明，ChalcEA使His524的构象不稳定，这是已知hERα拮抗剂（包括4-OHT）的显著行为。此外，对基于药效团和对接筛选得到的10种最佳查耳酮衍生物进行了T47D细胞系测试。没有一种衍生物具有比ChalcEA更好的活性。建议在接下来的研究中进一步优化ChalcEA B环上的官能团。
结论
ChalcEA可能作为hERα的拮抗剂，因此作为一种潜在的抗癌剂值得进一步研究。
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