Notes
This doctoral dissertation aims to examine and elucidate the poorly understood molecular mechanisms of anticarcinogenic and neuroprotective effects of natural polyphenols as chemopreventive agents as well as in the role of suppressors of carcinogenesis and Alzheimer's disease, using innovative computational approaches.In the first part of the doctoral dissertation, we examined polyphenol 6-gingerol and the tripeptide glutathione as scavengers of nine ultimate genotoxic chemical carcinogens. Using quantum mechanical simulations, we obtained valuable insights into the proposed SN2 reaction mechanisms and the geometries of the corresponding reactants and transition states. The presented quantum-mechanical methodology has a high potential to become a standard tool for predicting the chemopreventive potential of various polyphenolic compounds as scavengers of chemical carcinogens of the epoxy type.In the second part of the doctoral dissertation, we investigated xanthohumol and its derivatives isoxanthohumol, 8-prenylnaringenin, and 6-prenylnaringenin as scavengers of aflatoxin B1 exo-8,9-epoxide. Using quantum mechanical simulations, we discovered the connection between the structure and the anticarcinogenic activity of the studied prenylflavonoids, as well as confirmed the validity of the proposed SN2 reaction mechanism. Reduction in aflatoxin B1-induced cytotoxicity and genotoxicity was also confirmed in vitro in human hepatocellular carcinoma HepG2 cell line after the addition of xanthohumol.In the third part of the doctoral dissertation, we developed a novel inverse molecular docking protocol, which identifies a narrow set of prioritized human protein targets of a selected polyphenolic compound. We were the first to successfully uncover the molecular mechanisms of curcumin's anticarcinogenic and neuroprotective activities, based on its binding affinity to specific human proteins involved in oncogenic and neurodegenerative signaling cascades. Moreover, the developed protocol possesses a high potential in pharmaceutical applications, as it represents a universal approach that can be used to explain the already observed as well as predict new potential biological effects of the studied lead compounds.In the fourth part of the doctoral dissertation, we performed molecular docking, molecular dynamics simulations, and binding free energy calculations to investigate inhibitory mechanisms of four dietary polyphenols against phosphodiesterase 4D, which represents a high-interest therapeutic target for the treatment of Alzheimer’s disease. The calculated binding free energies proved that curcumin, 6-gingerol, capsaicin, and resveratrol represent potential inhibitors of phosphodiesterase 4D, with curcumin exhibiting the highest inhibitory potency. With the combined computational approach, we for the first time obtained a mechanistic insight into the connection between the structure and neuroprotective activities of the four studied polyphenols, which is unattainable using laboratory experiments.In the fifth part of the doctoral dissertation, we presented extraction, distillation, and characterization methods for obtaining high-quality bioactive extracts, essential oils, and major bioactive polyphenols from rosemary as well as methods for determining their antioxidant, antimicrobial, anti-inflammatory, and anticarcinogenic potentials. With a comprehensive review of existing research and guidelines for further research, we laid the foundation for successful applications of extracts, essential oils, and numerous bioactive polyphenols from rosemary in the pharmaceutical and food industries.We firmly believe that presented in silico approaches as well as uncovered inhibitory mechanisms form a solid basis for faster and cheaper development of novel functional dietary supplements and drugs for the prevention and treatment of cancer and Alzheimer's disease with a potentially wider therapeutic window and fewer side effects.