Solvent Effects on the Valence UV-Vis Absorption Spectra of Topotecan Anticancer Drug in Aqueous Solution at Room Temperature: A Nanoseconds Time-scale TD-DFT/MD Computational Study

The low-lying valence electronic excitations of the topotecan anticancer drug, in two stable lactone forms, have been addressed in infinite dilute aqueous solution by combining time-dependent density functional theory calculations with nanoseconds time-scale classical molecular dynamics simulations at 298 K. The effects of the surrounding and fluctuating classical environment on the investigated topotecan forms are included in a perturbed electronic Hamiltonian, which is computed, and then diagonalized, at each frame stored during the molecular dynamics sampling in explicit solution. Current results clearly indicate that, at moderately acidic and physiological conditions, the valence UV-vis absorption spectra of topotecan drug are strongly affected by the surrounding dielectric media and by its perturbing trajectory as arising from finite-temperature fluctuations and supramolecular interactions. Furthermore, the extension of the proposed computational study to hydrated topotecan complexes in liquid water shows that all of the experimentally detected UV-vis spectroscopic features in solution are accurately reproduced only when direct solute-solvent intermolecular interactions are also explicitly taken into account in our simulating scenario. Finally, the present investigation opens up a chance regarding the computational prediction of the UV-vis absorption spectra of topotecan interacting, in silico, with the topoisomerase-DNA binary complex in physiological conditions (i.e., water dilute solution, room temperature).