Interactions of the aquated forms of the anticancer drug AMD443 with DNA purine bases: A detailed computational approach

The mechanism of substitution reaction of chloroaqua and diaqua complexes, trans-[Pt(2-pic)(NH3)Cl(H2O)]+ and trans-[Pt(2-pic)(NH3)(H2O)2]2+, which are formed after intracellular aquation of the anticancer drug AMD443, with the DNA purine bases guanine (G) and adenine (A) were studied computationally by TST–DFT method. The aqua ligand of such complexes undergoes ligand exchange reactions with N7 atom of G or A as the preferential nucleophilic centers. The predominance of attack toward G over A has been observed. We have estimated the degree of trigonality (τ) and synchronicity (σy) for all transition states. The computed free energy of activation (ΔG‡(aq)) for chloroaqua complexes are 15.1 kcal/mol and 18.5 kcal/mol for guanine and adenine, respectively. The respective values for the diaqua complexes are higher. For the bifunctional adduct we observed that GG adduct with head-to-head (HH) conformation prefers over GA adduct by ≈8.5 kcal/mol and over the GG head-to-tail (HT) conformation by ≈0.9 kcal/mol.