Molecular and Therapeutic Insights of Alpha-Lipoic Acid as a Potential Molecule for Disease Prevention

Abstract

Alpha-lipoic acid is an organic, sulfate-based compound produced by plants, humans, and animals. As a potent antioxidant and a natural dithiol compound, it performs a crucial role in mitochondrial bioenergetic reactions. A healthy human body, on the other hand, can synthesize enough α-lipoic acid to scavenge reactive oxygen species and increase endogenous antioxidants; however, the amount of α-lipoic acid inside the body decreases significantly with age, resulting in endothelial dysfunction. Molecular orbital energy and spin density analysis indicate that the sulfhydryl (-SH) group of molecules has the greatest electron donating activity, which would be responsible for the antioxidant potential and free radical scavenging activity. α-Lipoic acid acts as a chelating agent for metal ions, a quenching agent for reactive oxygen species, and a reducing agent for the oxidized form of glutathione and vitamins C and E. α-Lipoic acid enantiomers and its reduced form have antioxidant, cognitive, cardiovascular, detoxifying, anti-aging, dietary supplement, anti-cancer, neuroprotective, antimicrobial, and anti-inflammatory properties. α-Lipoic acid has cytotoxic and antiproliferative effects on several cancers, including polycystic ovarian syndrome. It also has usefulness in the context of female and male infertility. Although α-lipoic acid has numerous clinical applications, the majority of them stem from its antioxidant properties; however, its bioavailability in its pure form is low (approximately 30%). However, nanoformulations have shown promise in this regard. The proton affinity and electron donating activity, as a redox-active agent, would be responsible for the antioxidant potential and free radical scavenging activity of the molecule. This review discusses the most recent clinical data on α-lipoic acid in the prevention, management, and treatment of a variety of diseases, including coronavirus disease 2019. Based on current evidence, the preclinical and clinical potential of this molecule is discussed.

Supplementary information: The online version contains supplementary material available at 10.1007/s43450-023-00370-1.

Keywords: Electronic structure study; Gut microbiota; Molecular targets; Neuroprotection; Pharmacological potential; Thioctic acid.

Fig. 1

Cellular and molecular functions of α-lipoic acid

Fig. 2

Mechanism for antioxidant properties of α-lipoic acid

Fig. 3

Molecular targets of α-lipoic acid against various diseases

Fig. 4

Molecular electronic potential plots of the two enantiomers of α-lipoic acid. a S-α-lipoic; b R-α-lipoic acid, the biologically active isomer

Fig. 5

HOMO–LUMO plots of the two enantiomers of α-lipoic acid a S-enantiomer; b R-enantiomer

Fig. 6

Lipoic acid and its reduced form, dihydrolipoic acid, with the most common metabolites