Computational Studies of Hypericin and Porphyrin Derivatives for Photodynamic Therapy - Spectra, Membrane Simulations, and Protein Interactions

Photosensitizing compounds with potential application in anticancer treatment with photodynamic therapy were investigated by means of computational methods in the studies presented in this thesis. Hypericin and brominated derivatives were studied regarding possible reaction mechanisms and interactions with membranes and proteins. Monobrominated hypericin was found to possibly dissociate in an oxygen-independent reaction, providing an alternative pathway that can produce radical species in tumours. Hypericin, mono- and tetrabrominated hypericin showed strong preference for lipid membranes, in which monobrominated hypericin displayed the highest permeation, indicating that this molecule would have the highest probability to enter a cell through diffusion. Hypericin molecules that have the ability to reach the interior of a cell are prone to initiate damage to intracellular molecular targets, such as the endoplasmic reticulum Ca2+ ATPase SERCA, with which hypericin was found to interact strongly. Benchmarking studies of functionals used in TD-DFT were performed in order to determine suitable methodologies for predicting absorption spectra of photosensitizing tetrapyrrole compounds. The studies provide an evaluation of the potential to use long-range corrected functionals in computer-assisted design of photosensitizers for photodynamic therapy. Based on the results from the benchmarking studies, modified chlorin derivatives with strong absorption in the therapeutic window of photodynamic therapy were designed, representing suitable starting points for further experimental evaluation. The presented studies of hypericin and tetrapyrrole compounds provide detailed knowledge on possible reaction mechanisms, spectroscopic properties, and interactions with biomolecular systems. This information contributes to deep insight into the action of these compounds and can be of great importance in the development of photodynamic agents with improved therapeutic properties