Computational modeling predicts potential effects of the herbal infusion "horchata" against COVID-19

Abstract

Bioactive plant-derived molecules have emerged as therapeutic alternatives in the fight against the COVID-19 pandemic. In this investigation, principal bioactive compounds of the herbal infusion "horchata" from Ecuador were studied as potential novel inhibitors of the SARS-CoV-2 virus. The chemical composition of horchata was determined through a HPLC-DAD/ESI-MSⁿ and GC-MS analysis while the inhibitory potential of the compounds on SARS-CoV-2 was determined by a computational prediction using various strategies, such as molecular docking and molecular dynamics simulations. Up to 51 different compounds were identified. The computational analysis of predicted targets reveals the compounds' possible anti-inflammatory (no steroidal) and antioxidant effects. Three compounds were identified as candidates for M^pro inhibition: benzoic acid, 2-(ethylthio)-ethyl ester, l-Leucine-N-isobutoxycarbonyl-N-methyl-heptyl and isorhamnetin and for PL^pro: isorhamnetin-3-O-(6-Orhamnosyl-galactoside), dihydroxy-methoxyflavanone and dihydroxyphenyl)-5-hydroxy-4-oxochromen-7-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid. Our results suggest the potential of Ecuadorian horchata infusion as a starting scaffold for the development of new inhibitors of the SARS-CoV-2 M^pro and PL^pro enzymes.

Keywords: COVID-19; Docking; Gene ontology; Herbal infusion; Horchata infusion; Molecular dynamics; SARS-CoV-2.

Fig. 1

Predicted free energies of binding of the 50 compounds to the SARS-CoV-2 M^pro (A) and PL^pro (B) enzymes. The color scale goes from green (best) to red (worst) ΔG of binding. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 2

Predicted binding modes of compounds 48, 46 and 31 to the SARS-CoV-2 M^pro enzyme. ln the lefthand figures, oxygen atoms are depicted as red, nitrogen atoms blue, sulfur atoms yellow, and the carbon atoms of the ligands orange. The same coloring scheme was applied to the interaction diagrams (right), while carbon atoms are colored black on them. These diagrams depict all atoms for the receptor residues forming hydrogen bonds with the ligands. Only receptor residues interacting with the ligands in at least 50% of the analyzed MD snapshots are labeled in the lefthand figures and represented in the interaction diagrams. The compounds are: 7-Acetyl-6-ethyl-1,1,4,4-tetramethyltetralin (48), l-Leucine, N-isobutoxycarbonyl-N-methyl-, heptyl ester (46), and Isorhamnetin (31). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 3

Predicted binding modes of compounds 30, 26 and 40 to the SARS-CoV-2 PL^pro enzyme. In the lefthand figures, oxygen atoms are colored red, nitrogen atoms blue, sulfur atoms yellow, and the carbon atoms of the ligands orange. The same coloring scheme was applied to the interaction diagrams (right), while carbon atoms are colored black on them. These diagrams depict all atoms for the receptor residues forming hydrogen bonds with the ligands. Only receptor residues interacting with the ligands in at least 50% of the analyzed MD snapshots are labeled in the lefthand figures and represented in the interaction diagrams. The compounds are: Isorhamnetin-3-O-(6-O-rhamnosyl-galactoside) (30), 5,7-dihydroxy-4′-methoxyflavanone (26), and (2S,3S,4S,5R,6S)-6-[2-(3,4- Dihydroxyphenyl)-5- hydroxy-4-oxochromen-7- yl]oxy-3,4,5- trihydroxyoxane-2- carboxylic acid (40). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)