In Vitro Anti-Oxidant, In Vivo Anti-Hyperglycemic, and Untargeted Metabolomics-Aided-In Silico Screening of Macroalgae Lipophilic Extracts for Anti-Diabetes Mellitus and Anti-COVID-19 Potential Metabolites.

COVID-19 patients with comorbid DM face more severe outcomes, indicating that hyperglycemic conditions exacerbate SARS-CoV-2 infection. Negative side effects from existing hyperglycemia treatments have urged the need for safer compounds. Therefore, sourcing potential compounds from marine resources becomes a new potential approach. Algal lipids are known to possess beneficial activities for human health. However, due to limitations in analyzing large amounts of potential anti-hyperglycemic and anti-COVID-19-related marine metabolites, there is an increasing need for new approaches to reduce risks and costs. Therefore, the main aim of this study was to identify potential compounds in macroalgae , , and lipophilic extracts for treating DM and COVID-19 by an integrated approach utilizing in vitro anti-oxidant, in vivo anti-hyperglycemic, and metabolomic-integrated in silico approaches. Among them, and showed potential anti-hyperglycemic activity, with showing the highest anti-oxidant activity. A GC-MS-based untargeted metabolomic analysis was used to profile the lipophilic compounds in the extracts followed by an in silico molecular docking analysis to examine the binding affinity of the compounds to anti-DM and anti-COVID-19 targets, e.g., α-amylase, α-glucosidase, ACE2, and TMPRSS2. Notably, this study reveals for the first time that steroid-derived compounds in the macroalgae had higher binding activity than known ligands for all the targets mentioned. Studies on drug likeliness indicate that these compounds possess favorable drug properties. These findings suggest the potential for these compounds to be further developed to treat COVID-19 patients with comorbid DM. The information in this study would be a basis for further in vitro and in vivo analysis. It would also be useful for the development of these candidate compounds into drug formulations.