Investigation on the impact of solvent on the photochemical properties of the photoactive anticancer drug Vemurafenib: A computational study

Abstract

Rationalizing the photochemical behavior of a photosensitive drug in terms of molecular properties is necessary toward understanding related potential phototoxicity. Here, we report on the effect of the molecular microenvironment on the physicochemical and photochemical properties of a first-line anticancer drug Vemurafenib. Time-dependent density functional (TD-DFT) calculations were performed to simulate the absorption spectra of Vemurafenib in implicit solvents of various polarity and hydrogen bonding capabilities. The obtained results revealed polarity-dependent spectral characteristics indicative of the influence of the microenvironment on the structural properties of the drug. In particular, a notable enhancement in the oscillation strength of the main electronic transition, namely HOMO→LUMO, was observed in polar solvents. These effects can be attributed to the enhanced charge delocalization across the molecule comprising the lone-pairs of the heteroatoms. Moreover, the obtained DFT results suggest that such electronic transition can exhibit a major influence on the photochemical properties of the drug. Furthermore, the effect of intermolecular hydrogen bonding between Vemurafenib and its microenvironment was explicitly investigated employing the same level of TD-DFT calculations. Obtained results demonstrated a substantial effect for such interactions on the spectral properties of the drug. In addition, the NBO analysis revealed physicochemical properties for the explicit hydrogen-bonded complexes of Vemurafenib with dimethylformamide molecules that are well in line with the TD-DFT results. These NBO results revealed substantial changes in the structural properties of the drug indicative of the influence of the intermolecular hydrogen bonding on its photochemical properties; this includes a notable change in the charge density of selected atoms as well as enhanced electronic transitions. The results reported herein provide insights concerning understanding the photochemical behavior of Vemurafenib in biologically mimicked microenvironments at the molecular level, which can be utilized in future efforts toward reducing induced phototoxicity.