Estudo computacional da termodinâmica e cinética das reações da cisplatina com a glutationa

Abstract

The studies on metal complexes for use in cancer chemotherapy have greatly increased since the discovery of the biological activity of cis-diamminedichloroplatinum(II), better known as cisplatin. Cisplatin is effective in cancer treatment, and its mechanism of action is based on the platinum-DNA binding, which interferes with cellular transcription and replication processes, leading to cell death or apoptosis. However, certain tumors originally sensitive to cisplatin develop chemoresistance, which is the main limitation in the clinical use of cisplatin and is generally multifactorial. Glutathione (GSH) is often considered the primary contributor to the sequestration of cisplatin due to its high intracellular concentration. Therefore, most of the interaction modulates toxicity, preventing cisplatin from interacting with DNA. In this work, the reactions of cisplatin and its hydrolyzed species with glutathione were studied, and the structures of the reacting species, products, and intermediate species, where the main intermolecular interactions involved in the reaction were observed, were characterized. To represent the studied processes, numerous DFT M062X calculations were performed, with the 6-31G(d,p) function and Lanl2dz as the pseudopotential for the platinum atom. Different conformers of glutathione were evaluated, and the GLUCα-C-C-C(COOH) and CYSN-C-C-N(CH2COOH) dihedrals and the terminal hydroxyls of glutamate and glycine were the parameters used to categorize and differentiate conformations. Three conformations were found, where the conformational population for the structures was I) 33.60%, II) 33.44%, III) 32.97%. The transition states of the first and second steps of the reactions were determined, where the conformations assumed by glutathione were directly related to the calculated energy parameters. Through the transition states, IRC calculations for reaction A were performed, and the conformation of GSH, the GLUCα-C-C-C(COOH)=-57.8° and CYSN-C-C-N(CH2COOH)=52.8° dihedrals, and the distances between the hydrogen atoms of the terminal hydroxyl groups (GLU-GLY) were evaluated, which was 9.444 Å. Comparatively, the product obtained via chemical intuition had GLUCα-C-C-C(=O)=-57.9° and CYSN-C-C-N(GLY)=58.21° and the distances between the glutamate and glycine acid groups were 3.970 Å, which is characteristic of a closed conformation.