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.

The mechanism of reaction of chloroaqua and diaqua complexes, trans-[Pt(2-pic)(NH3)Cl(H2O)]+, and trans-[Pt(2-pic)(NH3)(H2O)2]2+ of the anticancer drug AMD443 with the DNA purine bases guanine (G) and adenine (A) were studied computationally. In these reactions N7 atom of G or A acts as the preferential nucleophilic centers. The predominance of attack of G over A has been established for these complexes..Figure optionsDownload as PowerPoint slideHighlights
► Reaction mechanism of the hydrated drug AMD443 has been studied by DFT–TST method.
► A number of H-bonded networks create some reactant complexes and reaction paths.
► Transition state structures for all the paths are structurally trigonal-bipyramid.
► Degree of trigonality of TS and synchronicity of reaction paths computed.
► The preferential attack toward guanine over adenine has been established.