The Interaction of the Microtubule Targeting Anticancer Drug Colchicine with Human Glutathione Transferases

Author(s): Georgios Premetis, Panagiotis Marugas, Georgios Fanos, Dimitrios Vlachakis, Evangelia G. Chronopoulou, Fereniki Perperopoulou, Kashyap Kumar Dubey, Pratyoosh Shukla, Ahmed Ibrahim Foudah, Magdy Mohamed Muharram, Mohammed F. Aldawsari, Anastassios C. Papageorgiou, Nikolaos E. Labrou*

Journal Name: Current Pharmaceutical Design

Volume 26 , Issue 40 , 2020

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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.

Keywords: Cancer, colchicine, glutathione transferase, multi-drug resistance, Phase II detoxification enzymes, antimitotic.

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Article Details

Year: 2020
Published on: 27 November, 2020
Page: [5205 - 5212]
Pages: 8
DOI: 10.2174/1381612826666200724154711
Price: $65

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