Multilevel Computational Assessment of Chalcogen Functionalized <i>Aloe vera</i> Polyphenols as Next-Generation Antioxidants

Oxidative stress arising from excessive generation of free radical species in biological systems remains a major concern associated with several pathological conditions, thereby driving continuous interest in the development of effective antioxidants. Among various natural polyphenol-rich sources, Aloe vera is recognized as an important reservoir of bioactive antioxidant compounds. In the present study, five major polyphenols derived from Aloe vera were structurally modified through Sulphur and Selenium substitution at the hydroxyl and carbonyl functionalities to enhance their antioxidant potential. The changes in the thermodynamic parameters such as bond dissociation enthalpy, ionization potential, proton dissociation enthalpy, and electron transfer enthalpy were evaluated using density functional theory to elucidate the antioxidant mechanisms of the designed derivatives through the Hydrogen Atom Transfer, Single Electron Transfer followed by Proton Transfer, and Sequential Proton Loss followed by Electron Transfer pathways. Electronic properties and reactivity were further explored using frontier molecular orbital, molecular electrostatic potential, natural bond orbital, total density of states, transition state, and spin density distribution analyses. In addition, pharmacokinetic profiling was performed to evaluate the drug-likeness and biological suitability of the compounds. Molecular docking studies were conducted against the allosteric site of the antioxidant enzyme superoxide dismutase to investigate possible interactions that could enhance enzymatic activity through allosteric modulation. The computational results consistently demonstrated that Selenium-substituted derivatives exhibited the highest antioxidant activity, followed by Sulphur-substituted compounds, outperforming the parent molecules as well as standard antioxidant references including trans-Resveratrol, Gallic acid, and Fumaric acid. These findings reveal that chalcogen substitution can significantly improve the antioxidant efficiency of Aloe vera polyphenols and highlights the potential of Selenium-containing derivatives as promising candidates for the development of next generation antioxidants.