In order to examine the origin of the drug action and design new DNA/RNA-targeted drugs, the cooperativity effect involving drug-DNA/RNA intermolecular interaction in ketoprofen⋯cytosine⋯H2O ternary system were investigated by the B3LYP, B3LYP-D3, and MP2 methods with the 6-311++G(2d,p) basis set. The thermodynamic cooperativity was also evaluated at 310.15 K. The N-H⋯O, O-H⋯O, O-H⋯N, C-H⋯N, and C-H⋯O H bonds coexist in ternary complexes. The intermolecular interactions obtained by B3LYP-D3 are close to those calculated by MP2. The steric effects and van der Waals interactions have little influence on the cooperativity effects. The anti-cooperativity effect in ket⋯cyt⋯H2O is far more notable than the cooperativity effect, and the stability of the cyclic structure with anti-cooperativity effect is higher than that of the linear structure with cooperativity effect, as is confirmed by the AIM (atoms in molecules) and RDG (reduced density gradient) analysis. Thus, it can be inferred that, in the presence of H2O, the anti-cooperativity effect plays a dominant role in the drug-DNA/RNA interaction, and the nature of the hydration in the binding of drugs to DNA/RNA bases is the H-bonding anti-cooperativity effect. Furthermore, the drug always links simultaneously with DNA/RNA base and H2O, and only in this way can the biological activity of drugs play a role. In most cases, the enthalpy change is the major factor driving the cooperativity, as is different from most of biomacromolecule complexes.
Keywords: H-bonding cooperativity effect; MP2; cytosine; drug–DNA/RNA interaction; ketoprofen.