Blue moon ensemble simulation of aquation free energy profiles applied to mono and bifunctional platinum anticancer drugs

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Aquation free energy profiles of neutral cisplatin and cationic monofunctional derivatives, including triaminochloroplatinum(II) and cis-diammine(pyridine)chloroplatinum(II), were computed using state of the art thermodynamic integration, for which temperature and solvent were accounted for explicitly using density functional theory based canonical molecular dynamics (DFT-MD).

• For all the systems the "inverse-hydration" where the metal center acts as an acceptor of hydrogen bond has been observed.
• This has motivated to consider the inversely bonded solvent molecule in the definition of the reaction coordinate required to initiate the constrained DFT-MD trajectories.
• We found that there exists little difference in free enthalpies of activations, such that these platinum-based anticancer drugs are likely to behave the same way in aqueous media.