The Interaction of Schistosoma Japonicum Glutathione Transferase with Cibacron Blue 3GA and its Fragments
| Autor: | Magdy Mohamed Muharram, Dimitrios Vlachakis, Mohamed Hamed Alqarni, Nikolaos E. Labrou, Anastassios C. Papageorgiou, Ahmed I. Foudah, Michalis Platis |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
chemistry.chemical_classification
Steric effects 0303 health sciences biology Chemistry Schistosoma japonicum biology.organism_classification 01 natural sciences 0104 chemical sciences 010404 medicinal & biomolecular chemistry 03 medical and health sciences Enzyme Biochemistry Drug Discovery Mole Potency Enzyme kinetics Binding site IC50 030304 developmental biology |
| Zdroj: | Medicinal Chemistry. 17:332-343 |
| ISSN: | 1573-4064 |
| DOI: | 10.2174/1573406416666200403074742 |
| Popis: | Background: The 26kDa glutathione transferase (GST, EC 2.5.1.18) from Schistosoma japonicum (SjGST) is recognized as the major detoxification enzyme of S. japonicum, a pathogenic helminth causing schistosomiasis. Objective: In the present study, the interaction of the chlorotriazine dye Cibacron blue 3GA (CB3GA) and its structural analogues with SjGST was investigated. The work aimed to shed light on the non-substrate ligand-binding properties of the enzyme. Methods: Kinetic inhibition analysis, affinity labelling experiments and molecular modelling studies were employed. Results: The results showed that CB3GA is a potent inhibitor (IC50 0.057 ± 0.003 μM) towards SjGST. The enzyme was specifically and irreversibly inactivated by the dichlorotriazine-analogue of CB3GA (IC50 0.190 ± 0.024 μM), following a biphasic pseudo-first-order saturation kinetics with approximately 1 mol of inhibitor per mol of the dimeric enzyme being incorporated. All other monochlorotriazine analogues behave as reversible inhibitors with lower inhibition potency (IC50 5.2-82.3 μM). Kinetic inhibition studies, together with molecular modelling and molecular dynamics simulations, established that the CB3GA binding site overlaps both the G- and H-sites. Both hydrophobic/ polar interactions, as well as steric effects, have decisive roles in determining the inhibitory strength of CB3GA and its analogues. Conclusion: The results of the present study might be useful in future drug design and development efforts towards SjGST. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|