Abstract
Cisplatin is still a first-line agent in cancer treatment due to its effectiveness. Despite the large body of research concerning this drug, the role of explicit water molecules in its mechanism remains uncertain. We addressed the addition of cisplatin with the nitrogenous DNA bases adenine and guanine, with an emphasis on the impact of explicit microsolvation on every step of the action pathway of this pharmaceutical. We used electronic structure calculations to explore the energetics of the key reactions of this mechanism. We also exploited state-of-the-art methods of wave function analyses, namely, the Quantum Theory of Atoms in Molecules and the Interacting Quantum Atoms partition, to explore the chemical bonding throughout such chemical reactions. Our results reveal that microsolvation significantly differently affects electronic and Gibbs free activation energies, as previously reported (F.P. Cossio et al. ChemPhysChem, 17, 3932, 2016). The changes in activation energies are consistent with Hammond's postulate in terms of the changes in the chemical bonding scenario between reactants and transition states. Overall, we provide an in-depth description of the importance of the surrounding water molecules of cisplatin, which aids in understanding the mechanism of pharmaceuticals in the pursuit of more effective cancer treatments.