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Cisplatin interaction with cysteine and methionine, a theoretical DFT study
Tomás Zimmermann1, Michal Zeizinger, Jaroslav V Burda
1Department of Chemical Physics and Optics, Faculty of Mathematics and Physics, Charles University, Ke Karlovu 3, 121 16 Prague 2, Czech Republic.
Journal of Inorganic Biochemistry
|September 27, 2005
Summary
Cisplatin interacts more strongly with cysteine than methionine, forming stable platinum-sulfur bonds. This explains why cysteine adducts are irreversible, while methionine adducts are reversible.
Area of Science:
- Inorganic Chemistry
- Computational Chemistry
- Medicinal Chemistry
Background:
- Cisplatin is a crucial chemotherapy drug.
- Understanding its interactions with biological molecules is vital for drug development.
- Sulfur-containing amino acids like cysteine and methionine are potential binding sites.
Purpose of the Study:
- To investigate the interactions between hydrated cisplatin complexes and cysteine/methionine.
- To determine the binding energies and stability of these adducts.
- To correlate binding characteristics with the reversibility of cisplatin adducts.
Main Methods:
- Density Functional Theory (DFT) calculations using the B3LYP functional.
- Modeling of isolated molecules and supermolecular approaches.
- Estimation of Bond Dissociation Energies (BDE) and association energies.
Main Results:
- Monodentate complex formation is exothermic, with Pt-S coordination in cysteine yielding the highest BDE (114 kcal/mol).
- Cysteine adducts exhibit significantly stronger bonding than methionine adducts (approx. 40 kcal/mol difference).
- Chelate structure formation is exothermic for hydroxo-cisplatin, stabilized by interactions with released water.
Conclusions:
- The strong Pt-S bond in cisplatin-cysteine adducts explains their irreversibility.
- Weaker interactions in cisplatin-methionine adducts correlate with their reversibility.
- Computational modeling provides insights into cisplatin's mechanism of action and drug resistance.