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. 2023 Nov 27;13(12):1177.
doi: 10.3390/metabo13121177.

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

Anggit Listyacahyani Sunarwidhi  1   2 , Wahyu Rahmaniar  3 , Eka Sunarwidhi Prasedya  2   4 , Hasriaton Padmi  2 , Sri Widyastuti  5 , Kukuh Waseso Jati Pangestu  2 , Bq Tri Khairina Ilhami  2 , Ervina Handayani  1 , Ni Wayan Putri Utami  1 , Farreh Alan Maulana  1 , Muhammad Syach Maulad Ichfa  1 , Ari Hernawan  6
Affiliations

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

Anggit Listyacahyani Sunarwidhi et al. Metabolites. .

Abstract

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 Sargassum cristaefolium, Tricleocarpa cylindrica, and Ulva lactuca 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, S. cristaefolium and T. cylindrica showed potential anti-hyperglycemic activity, with S. cristaefolium 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 T. cylindrica 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.

Keywords: COVID-19; diabetes mellitus; lipophilic compounds; macroalgae; metabolomics-aided in silico.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Workflow of in silico molecular docking analysis.
Figure 2
Figure 2
In vivo anti-hyperglycemic analysis of Sargassum cristaefolium, Tricleocarpa cylindrica, and Ulva lactuca on alloxan-induced diabetic rats. NDM = non-diabetes mellitus group; AL = alloxan-induced diabetic rats. Two-way ANOVA analysis with Dunnett’s multiple comparison test, * p-value < 0.05; ** p-value < 0.01; significance toward Alloxan-induced diabetic rats.
Figure 3
Figure 3
Gas Chromatography–Mass Spectrometry (GC-MS) chromatogram of (A) Sargassum cristaefolium lipophilic extract; (B) Tricleocarpa cylindrica lipophilic extract; and (C) Ulva lactuca lipophilic extract.
Figure 4
Figure 4
Binding affinity value of Sargassum cristaefolium, Tricleocarpa cylindrica, and Ulva lactuca lipophilic compounds toward anti-DM and anti-COVID-19 target proteins (the colored lines represent the macroalgae—brown line: Sargassum cristaefolium; red line: Tricleocarpa cylindrica; and green line: Ulva lactuca).
Figure 5
Figure 5
Chemical structure of compounds detected in red macroalga Tricleocarpa cylindrica with anti-diabetes mellitus and anti-COVID-19 activities: (A) Compound 1: Estra-1,3,5(10)-trien-17-β-ol-17-α-butadinyl-3-methoxy, (B) Compound 2: 17-(1,5-dimethyl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17,tetradecahydro-1H-cyclopenta(a)phenanthrene-3-ol, and (C) Compound 3: Stigmasta-5,24(28)-dien-3-ol, (3β,24Z)-.
Figure 6
Figure 6
The molecular docking results and the chemical bond ligand–protein interaction of native ligands (positive controls) with the target proteins: (A) acarbosa with α-amylase; (B) acarbosa with α-glucosidase; (C) captopril with ACE2; and (D) nafamostat with TMRPSS2.
Figure 7
Figure 7
The molecular docking results and the chemical bond ligand–protein interaction of Estra-1,3,5(10)-trien-17-β-ol-17-α-butadinyl-3-methoxy (Compound 1) detected in Tricleocarpa cylindrica against the diabetes mellitus (DM) and COVID-19-related proteins (A) α-glucosidase, (B) α-amylase, (C) ACE2, and (D) TMRPSS2.
Figure 8
Figure 8
The molecular docking results and the chemical bond ligand–protein interaction of 17-(1,5-dimethylhexyl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H cyclopenta[a]phenanthren-3-ol (Compound 2) detected in Tricleocarpa cylindrica against the diabetes mellitus (DM) and COVID-19-related proteins (A) α-glucosidase, (B) α-amylase, (C) ACE2, and (D) TMRPSS2.
Figure 9
Figure 9
The molecular docking results and the chemical bond ligand–protein interaction of Stigmasta-5,24(28)-dien-3-ol,(3β,24Z)- (Compound 3) in Tricleocarpa cylindrica against the diabetes mellitus (DM) and COVID-19-related proteins (A) α-glucosidase, (B) α-amylase, (C) ACE2, and (D) TMRPSS2.
Figure 10
Figure 10
Bioavailability radar and boiled-egg diagram of the compounds’ physicochemical properties. (A) Compound 1: Estra-1,3,5(10)-trien-17-β-ol-17-α-butadinyl-3-methoxy; (B) Compound 2: 17-(1,5-Dimethylhexyl)-10,13-dimethyl-2,3,4,7,8,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-ol; (C) Compound 3: Stigmasta-5,24(28)-dien-3-ol, (3β,24Z)-; and (D) boiled-egg diagram of all three compounds.
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