In Silico Perlustration of Elementary Radical Reactions: from Antioxidant Activity to Ferroptosis Inhibition

In this Thesis, insights into the antioxidant activity of radical reactions have been provided in silico, trough Density Functional Theory (DFT) calculations. Antioxidant activity is carried out by elementary radical reactions, including the direct quenching of free radicals, i.e., scavenging mechanisms. Both mechanistic aspects and application to biologically relevant systems have been analyzed. Particularly, the distinction between concerted proton electron transfer and hydrogen atom transfer have been highlighted, as well as the electronic and orbital factors controlling this kind of reactivity in model systems. Then, a quantitative systematic approach has been used to investigate the scavenging potential of model polyphenolic compounds, obtaining topological insights into their activity. The second part of this Thesis deals with applications to real systems, such as natural molecules, approved drugs, new synthetic compounds and their antioxidant activity. Moreover, validated Machine Learning methodologies have been applied to predict the scavenging potential of phenolic molecules, providing a tool for the initial screening of thermodynamic feasibility. Lastly, a molecular mechanism for ferroptosis inhibition has been proposed for well-established inhibitors and a newly discovered anti-ferroptotic drug. Overall, the mechanistic descriptions explored in this Thesis can provide rationalization of the chemistry behind the antioxidant activity as well as ideas and tools for drug design.