Characterizing Pt-derived anticancer drugs from first principles: the case of oxaliplatin in aqueous solution

The molecular compound ethyldiamine-oxalatoplatinum(II), EDO-Pt, is used as a model to study the oxaliplatin anticancer drug in aqueous solution by means of ab initio computer simulation. Gas-phase structure optimizations have been performed for both oxaliplatin and its EDO-Pt mimic along with Car-Parrinello molecular dynamics simulations of EDO-Pt in gas phase and in aqueous solution. The coordination of Pt(II) is square-planar on average, with Pt-N and Pt-O(I) distances of 2.04 A in solution. The diamine ligand has a bent structure, while the oxalate ligand is planar on average. The complex features a very rigid structure during the simulation and the charge distribution describes a dipole with its negative pole on the oxalate ligand and the positive pole on the Pt-diamine side. The solvation pattern of EDO-Pt is most well-defined around the amine and oxalate groups and is quantified by means of radial and spatial distribution functions of water molecules around the complex. Decomposition of radial distribution functions into their contributions from different regions (axial and equatorial) reveals an "anionic hydration" pattern of the metal cation by the solvent, which is analogous in nature to the bare Pt(II) aqua ion. A qualitative prediction on the kinetics of ligand exchange in oxaliplatin is derived based on its axial hydration pattern.