Laboratory of Enzyme Technology, Department of Biotechnology, School of Applied Biology and Biotechnology, Agricultural University of Athens, 75 Iera Odos Street, GR-11855-Athens, Greece.
Laboratory of Genetics, Department of Biotechnology, School of Food, Biotechnology and Development, Agricultural University of Athens, 75 Iera Odos Street, GR-11855-Athens, Greece.
Curr Pharm Des. 2020;26(40):5205-5212. doi: 10.2174/1381612826666200724154711.
Glutathione transferases (GSTs) are a family of Phase II detoxification enzymes that have been shown to be involved in the development of multi-drug resistance (MDR) mechanism toward chemotherapeutic agents. GST inhibitors have, therefore, emerged as promising chemosensitizers to manage and reverse MDR. Colchicine (COL) is a classical antimitotic, tubulin-binding agent (TBA) which is being explored as anticancer drug.
In the present work, the interaction of COL and its derivative 2,3-didemethylcolchicine (2,3-DDCOL) with human glutathione transferases (hGSTA1-1, hGSTP1-1, hGSTM1-1) was investigated by inhibition analysis, molecular modelling and molecular dynamics simulations.
The results showed that both compounds bind reversibly to human GSTs and behave as potent inhibitors. hGSTA1-1 was the most sensitive enzyme to inhibition by COL with IC50 22 μΜ. Molecular modelling predicted that COL overlaps with both the hydrophobic (H-site) and glutathione binding site (G-site) and polar interactions appear to be the driving force for its positioning and recognition at the binding site. The interaction of COL with other members of GST family (hGSTA2-2, hGSTM3-3, hGSTM3-2) was also investigated with similar results.
The results of the present study might be useful in future drug design and development efforts towards human GSTs.
谷胱甘肽转移酶（GSTs）是一类 II 相解毒酶，已被证明与化疗药物的多药耐药（MDR）机制有关。因此，GST 抑制剂已成为有前途的化疗增敏剂，可用于治疗和逆转 MDR。秋水仙碱（COL）是一种经典的抗有丝分裂、微管结合剂（TBA），目前正在作为抗癌药物进行探索。
在本工作中，通过抑制分析、分子建模和分子动力学模拟研究了 COL 及其衍生物 2,3-二去甲基秋水仙碱（2,3-DDCOL）与人类谷胱甘肽转移酶（hGSTA1-1、hGSTP1-1、hGSTM1-1）的相互作用。
结果表明，两种化合物均可与人类 GSTs 可逆结合，且具有较强的抑制作用。hGSTA1-1 对 COL 的抑制最敏感，IC50 为 22 μΜ。分子建模预测 COL 重叠于疏水性（H 位）和谷胱甘肽结合位（G 位），并且极性相互作用似乎是其在结合位定位和识别的驱动力。COL 与 GST 家族其他成员（hGSTA2-2、hGSTM3-3、hGSTM3-2）的相互作用也进行了类似的研究，得到了类似的结果。
本研究的结果可能对未来针对人类 GSTs 的药物设计和开发工作有用。
