The Interaction of the Microtubule Targeting Anticancer Drug Colchicine with Human Glutathione Transferases
| Autor: | Nikolaos E. Labrou, Georgios Fanos, Georgios Premetis, Evangelia G. Chronopoulou, Kashyap Kumar Dubey, Anastassios C. Papageorgiou, Magdy Mohamed Muharram, Panagiotis Marugas, Fereniki Perperopoulou, Pratyoosh Shukla, Mohammed F. Aldawsari, Ahmed I. Foudah, Dimitrios Vlachakis |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Drug media_common.quotation_subject Antineoplastic Agents Microtubules 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Microtubule Drug Discovery Humans Colchicine Binding site IC50 Glutathione Transferase media_common Pharmacology chemistry.chemical_classification Glutathione 030104 developmental biology Enzyme Biochemistry chemistry 030220 oncology & carcinogenesis Phase II Detoxification Glutathione binding |
| Zdroj: | Current Pharmaceutical Design. 26:5205-5212 |
| ISSN: | 1381-6128 |
| DOI: | 10.2174/1381612826666200724154711 |
| Popis: | Background: 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. Methods: 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. Results: 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. Conclusion: The results of the present study might be useful in future drug design and development efforts towards human GSTs. |
| Databáze: | OpenAIRE |
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