Antioxidant activity at the molecular level: exploring ways of action and computational tools to investigate them

Despite their apparent simplicity, antioxidants are involved in numerous and complex processes. Several key aspects of antioxidant chemistry are covered in this review. (I) Their ways of action, which include scavenging free radicals; inhibition of ˙OH production via Fenton-like reactions by chelating redox metals; the repair of oxidatively damaged biomolecules; and modulation of the antioxidant/oxidant enzymatic system. (II) The main mechanisms involved in those ways of action, such as formal hydrogen atom transfer (f-HAT), single electron transfer (SET), sequential proton lost electron transfer (SPLET), coupled-deprotonation-chelation mechanism (CDCM), oxidant-enzyme inhibition, and antioxidant-enzyme activation. (III) Computational tools aiming to explore antioxidant activity (AOX). They are roughly grouped into four categories, depending on the used strategy (calculated properties): reactivity descriptors, thermochemistry, kinetics and ligand-receptor interactions. The approaches used to estimate them include calculations based on activity-structure relationships, quantum mechanical calculations, and molecular docking. The limitations and advantages of using these strategies and approaches are discussed, as well as some key points related to mimicking the associated chemical reactions (e.g. the importance of solvent polarity, pH, and diffusion). (IV) Some future research directions in the field, like the computational design of new (more efficient) antioxidants, and the emerging role of machine learning (ML) and artificial intelligence (AI) as efficient strategies to address AOX, can contribute to gaining a more complete picture about the complex chemical behavior usually involved in the health benefits offered by antioxidants.