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 and Nikolaos E. Labrou* Pages 5205 - 5212 ( 8 )
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.
Cancer, colchicine, glutathione transferase, multi-drug resistance, Phase II detoxification enzymes, antimitotic.
Laboratory of Enzyme Technology, Department of Biotechnology, School of Applied Biology and Biotechnology, Agricultural University of Athens, 75 Iera Odos Street, GR-11855-Athens, Laboratory of Enzyme Technology, Department of Biotechnology, School of Applied Biology and Biotechnology, Agricultural University of Athens, 75 Iera Odos Street, GR-11855-Athens, Laboratory of Enzyme Technology, Department of Biotechnology, School of Applied Biology and Biotechnology, Agricultural University of Athens, 75 Iera Odos Street, GR-11855-Athens, Laboratory of Genetics, Department of Biotechnology, School of Food, Biotechnology and Development, Agricultural University of Athens, 75 Iera Odos Street, GR-11855-Athens, Laboratory of Enzyme Technology, Department of Biotechnology, School of Applied Biology and Biotechnology, Agricultural University of Athens, 75 Iera Odos Street, GR-11855-Athens, Laboratory of Enzyme Technology, Department of Biotechnology, School of Applied Biology and Biotechnology, Agricultural University of Athens, 75 Iera Odos Street, GR-11855-Athens, Bioprocess Engineering Lab, School of Biotechnology, Jawaharlal Nehru University, New Delhi, Enzyme Technology and Protein Bioinformatics Laboratory, Department of Microbiology, Maharshi Dayanand University, Rohtak, Haryana, Department of Pharmacognosy, College of Pharmacy, Prince Sattam Bin Abdulaziz University, 11942, Al Kharj, Department of Pharmaceutics, College of Pharmacy, Prince Sattam Bin Abdulaziz University, 11942, Alkharj, Department of Pharmaceutics, College of Pharmacy, Prince Sattam Bin Abdulaziz University, 11942, Alkharj, Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku 20521, Laboratory of Enzyme Technology, Department of Biotechnology, School of Applied Biology and Biotechnology, Agricultural University of Athens, 75 Iera Odos Street, GR-11855-Athens