Photophysical properties of meso-functionalized chlorins: A multiscale computational study for photodynamic therapy

In this work, we present a comprehensive computational investigation of a series of meso-aminated chlorin derivatives to evaluate their suitability as next-generation photodynamic therapy photosensitizers. Ground- and excited-state properties were analyzed using density functional theory (DFT) and time-dependent DFT calculations, indicating that all derivatives preserve the characteristic chlorin electronic structure, while meso-substitution modulates Q-band intensities. Their excited-state energy landscapes reveal favorable intersystem crossing pathways, supporting the favorable production of singlet oxygen(¹O₂). To evaluate their behavior in biologically relevant environments, classical molecular dynamics simulations were performed for water solution, β-cyclodextrin encapsulated complex, and in proximity of lipid bilayers. These results show that stable 1:2 host-guest complexes with β-cyclodextrin can be formed, supporting the suitability of a passive drug-delivery strategy, which should increase bioavailability. Besides, the photosensitizers preferentially localize at the membrane interface stabilized by favorable interactions with lipid headgroups. QM/MM calculations further confirm that their photophysical properties are largely preserved in these environments. Overall, our results highlight meso-aminated chlorins as promising candidates for PDT and demonstrate the effectiveness of a multiscale computational screening strategy for guiding the design of improved photosensitizers.