Binding of novel azole-bridged dinuclear platinum(II) anticancer drugs to DNA: Insights from hybrid QM/MM molecular dynamics simulations

Dinuclear Pt-containing compounds might be used to overcome the intrinsic and acquired cell resistance of widely used anticancer drugs such as cisplatin. Recently, the complexes [{cis-Pt(NH3)(2)}(2)(mu-OH)(mu-pz)](NO3)(2) (with pz = pyrazolate) (1), [{cis-Pt(NH3)(2)}(2)(mu-OH)(mu-1,2,3-ta-N(1),N(2))](NO3)(2) (with ta = 1,2,3-triazolate) (2), and the binding of 1 to d(CpTpCpTpG*pG*pTpCpTpCp) have been characterized. Here we provide the structural and electronic properties of the free drugs, of the intermediates of binding to guanine bases, and of the products, by performing DFT calculations. Our results show that in 2 an isomerization of the Pt-coordination sphere from N(2) to N(3) of the triazolate unit determines a thermodynamic stabilization of similar to 20 kcal/mol as a consequence of the formation of an allylic structure. In addition, hybrid quantum-classical molecular dynamics simulations of 1 and 2 DNA adducts have shed light on the structural distortions that the drugs induce to the DNA duplex. Our calculations show that the rise and the tilt of the two adjacent guanines are identical in the presence of 1 and 2, but they markedly increase when 2 binds in the N(l),N(3) fashion. In addition, the drugs do not provoke any kink upon binding to the double-stranded DNA, suggesting that they may act with a mechanism different than that of cisplatin. The accuracy of our calculations is established by a comparison with the NMR data for the corresponding complex with 1.