TY - JOUR
T1 - The interaction of the microtubule targeting anticancer drug colchicine with human glutathione transferases
AU - Premetis, Georgios
AU - Marugas, Panagiotis
AU - Fanos, Georgios
AU - Vlachakis, Dimitrios
AU - Chronopou-Lou, Evangelia G.
AU - Perperopoulou, Fereniki
AU - Dubey, Kashyap Kumar
AU - Shukla, Pratyoosh
AU - Foudah, Ahmed Ibrahim
AU - Mohamed Muharram, Magdy
AU - Aldawsari, Mohammed F.
AU - Papageorgiou, Anastassios C.
AU - Labrou, Nikolaos E.
N1 - Publisher Copyright:
© 2020 Bentham Science Publishers.
PY - 2020
Y1 - 2020
N2 - 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 che-motherapeutic 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 to-wards human GSTs.
AB - 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 che-motherapeutic 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 to-wards human GSTs.
KW - Cancer
KW - Colchicine
KW - Glutathione transferase
KW - Multi-drug resistance
KW - Phase II detoxification enzymes
UR - http://www.scopus.com/inward/record.url?scp=85096389969&partnerID=8YFLogxK
U2 - 10.2174/1381612826666200724154711
DO - 10.2174/1381612826666200724154711
M3 - Article
C2 - 32713331
AN - SCOPUS:85096389969
SN - 1381-6128
VL - 26
SP - 5205
EP - 5212
JO - Current Pharmaceutical Design
JF - Current Pharmaceutical Design
IS - 40
ER -
