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.