A closer look at the mode of binding of drug pemetrexed with CT-DNA.

The interaction of antifolate drug Pemetrexed () with CT-DNA has been studied by UV-Vis, fluorescence and circular dichroism spectroscopic techniques. The results of these spectroscopic studies in combination with viscosity measurements, voltammetric and KI quenching studies suggested a less-common mode of binding of with CT-DNA i.e. neither intercalation nor groove binding. Thus, metadynamic (MD) simulation is utilized to decipher the nature of binding of with CT-DNA. Analysis of free energy surfaces obtained in MD simulation, reveals that binds to the 3'- and 5'-ends of the DNA molecule. The thermodynamics of the interaction has been investigated by isothermal titration calorimetric experiment. The analysis shows that binds with CT-DNA strongly with a binding constant of 2.6x10 M and the process is found to be spontaneous ( - 12.84 kcal/mol). Further, positive values of enthalpy ( 6.09 cal/mol) and entropy ( 43.1 cal/mol) changes indicate that the binding is an enthalpically unfavourable and, instead, entropically driven process.Communicated by Ramaswamy H. Sarma.