Hydrolysis processes of novel anticancer transplatin analogues, trans-[PtCl2(NH3)(Am)](Am: nonplanar heterocycle piperidine or piperazine), were explored using the B3LYP hybrid functional and isoelectric focusing polarized continuum model (IEF-PCM). Stationary points on the potential energy surfaces for the first and second hydrolysis steps that proceed via a general SN2 pathway were fully optimized and characterized. The most remarkable structural variations in the hydrolysis process were found to occur in the equatorial plane of five-coordinate tri nal-bipyramidal (TBP) like structures of the intermediates and transition states. We obtained lower activation energies for trans-[PtCl2(NH3)(piperazine)] and a slightly higher activation energy for the first step and a slightly lower activation energy for the second step during the hydrolysis of trans-[PtCl2(NH3)(piperidine)] by comparison to previous work on the hydrolysis reactions of cisplatin. Our calculations suggest that this class of non-classical transplatin analogues with one nonplanar heterocyclic amine decreases the equatorial steric effect and the hydrolysis reaction barriers.