A detailed theoretical DFT study of the hydrolysis mechanism of orally active anticancer drug ZD0473

A hydrolysis process of the third generation orally active anticancer drug cis-[PtCl2(NH3)(2-picoline)], ZD0473 has been investigated using density functional theory. Pentacoordinated platinum transition state (TS) geometries along with other stationary points on potential energy surface were optimized and characterized including two different paths. Two explicit water molecules were included in the calculations to improve the solvation energies. To obtain accurate energies for the reaction surfaces, single-point energies were calculated by conductor-like polarisable continuum model (CPCM) using larger basis sets. The calculated results show that the second step is the rate-limiting process. The computed values of rate constant of different steps are in good agreement with the available experimental results.