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Abstract
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Since discovery of cisplatin, many efforts have been devoted to understand the mechanisms associated with its antitumor activity, which are nowadays quite well established [1]. The primary target of cisplatin is genomic DNA, and more especially the N7 position of guanine bases. Although there is no doubt that a Pt−N7 bond forms during initial attack, the exact structure of the monofunctional adduct is not well known [2]. A better understanding at the molecular level of the interactions between the Pt and DNA building blocks can be helpful in establishing a new strategy to design cisplatin analogues. In this work we report a theoretical study on the interaction of cisplatin and its four analogues (see Figure 1) with guanine, at BP86/def2-TZVP level of theory. Since the guanine has three possible binding sites with the transition metal, all isomers and conformers of drug-guanine complexes were optimized. The calculated relative free energies as well as interaction energies between drugs and guanine showed that the preferred binding site of guanine to Pt atom in studied drugs is N7. To investigate the nature of interactions between drugs and guanine, the EDA-NOCV and NBO analyses were also performed on drug-guanine complexes. The results of energy decomposition analysis show that the interaction between drugs and guanine is more electrostatic (~64% ) than covalent (~36%) and contribution of dispersion forces is ~5%.
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