Hydrolysis of cisplatin—a first-principles metadynamics study

摘要: Cisplatin, or cis-[Pt(NH(3))(2)Cl(2)], was the first member of a new revolutionary class anticancer drugs that is still used today for treatment wide variety cancers. The mode action cisplatin starts inside cell with hydrolysis Pt-Cl bonds to form Pt-aqua complex. solvent environment plays an essential role in many biochemical processes general, and expected have particular strong effect on activation (hydrolysis) derivatives. To investigate these effects, we studied explicit structures during by means Car-Parrinello molecular dynamics simulations. Since activated process, thus rare event simulation timescale, applied metadynamics sampling technique map out free energy landscape from which reaction mechanism are obtained. Our simulations show hydrogen bonding between water molecules metal complexes hydrolyzed product systems stronger than reactant system. In addition, profiles our shows second thermodynamically favourable, good agreement experimental results previous static density functional theory calculations. channels both steps rather flat, indicative continuous spectrum allowed mechanisms no preference either concerted dissociative associative pathways. Three five coordinated metastable intermediates do not exist aqueous solution.