Antioxidants: The Chemical Complexity Behind a Simple Word

What does the word antioxidant mean? Antioxidants are supposed to be nontoxic, versatile molecules capable of counteracting the damaging effects of oxidative stress (OS). Thus, when evaluating a candidate molecule as an antioxidant, several aspects should be considered. Antioxidants are more than free radical scavengers. Other routes may contribute to their protection against OS, including modulation of the redox enzymatic system, preventing free radical formation, and repairing oxidized biomolecules. However, molecules intended as antioxidants can also exhibit pro-oxidant or toxic effects. Thus, understanding the full complexity of their chemistry is crucial for making reliable predictions about their activity. This Account focuses on computational tools that can assist in addressing such a challenging task. Some key aspects to consider when evaluating the potential antioxidant activity (AOX) of a molecule using these tools are (i) its absorption, distribution, metabolism, and excretion (ADME) properties; (ii) the effects of solvent and pH on its speciation and reactivity; and (iii) the toxicity of the molecule, its metabolites, and the products of the reactions it may undergo in vivo. While computational tools offer unique insights into the chemoprotective effects of antioxidants, care must be taken when assessing the data they produce. For example, reactivity descriptors alone are seldom enough to make reliable predictions on AOX. The thermodynamics and kinetics of the reaction pathways contributing to it frequently rule the antioxidant performance. The selected method of calculation should be reliable for the task at hand, since it influences the numerical outcome. Using some references for comparison allows adding context to the calculated data. We have developed two protocols that can be combined to include those aspects into computational studies of antioxidants: the Quantum Mechanics-Based Test for Overall Free Radical Scavenging Activity (QM-ORSA) and the Computer-Assisted Design of Multifunctional Antioxidants Based on Chemical Properties (CADMA-Chem). Some examples of the application of these protocols are discussed herein. They illustrate the diversity of reaction mechanisms and environmental conditions that modulate AOX, considering potential benefits and risks. These protocols provide a theoretical framework for investigating AOX that allows straightforward comparison with experimental results. They can be applied to known antioxidants for gaining insight into observed behavior as well as in the development of new antioxidants intended as potential drug candidates for the treatment of OS-related diseases. This work aims to promote comprehensive investigations into antioxidant chemistry, contribute to the interpretation of the results obtained from calculations, and encourage the development of safe, efficacious molecules that ameliorate the harmful effects of OS on human health.