Critical Review of Plant-Derived Compounds as Possible Inhibitors of SARS-CoV-2 Proteases: A Comparison with Experimentally Validated Molecules

Abstract

Ever since coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, was declared a pandemic on March 11, 2020, by the WHO, a concerted effort has been made to find compounds capable of acting on the virus and preventing its replication. In this context, researchers have refocused part of their attention on certain natural compounds that have shown promising effects on the virus. Considering the importance of this topic in the current context, this study aimed to present a critical review and analysis of the main reports of plant-derived compounds as possible inhibitors of the two SARS-CoV-2 proteases: main protease (Mpro) and Papain-like protease (PLpro). From the search in the PubMed database, a total of 165 published articles were found that met the search patterns. A total of 590 unique molecules were identified from a total of 122 articles as potential protease inhibitors. At the same time, 114 molecules reported as natural products and with annotation of theoretical support and antiviral effects were extracted from the COVID-19 Help database. After combining the molecules extracted from articles and those obtained from the database, we identified 648 unique molecules predicted as potential inhibitors of Mpro and/or PLpro. According to our results, several of the predicted compounds with higher theoretical confidence are present in many plants used in traditional medicine and even food, such as flavonoids, carboxylic acids, phenolic acids, triterpenes, terpenes phytosterols, and triterpenoids. These are potential inhibitors of Mpro and PLpro. Although the predictions of several molecules against SARS-CoV-2 are promising, little experimental information was found regarding certain families of compounds. Only 45 out of the 648 unique molecules have experimental data validating them as inhibitors of Mpro or PLpro, with the most frequent scaffold present in these 45 compounds being the flavone. The novelty of this work lies in the analysis of the structural diversity of the chemical space among the molecules predicted as inhibitors of SARS-CoV-2 Mpro and PLpro proteases and the comparison to those molecules experimentally validated. This work emphasizes the need for experimental validation of certain families of compounds, preferentially combining classical enzymatic assays with interaction-based methods. Furthermore, we recommend checking the presence of Pan-Assay Interference Compounds (PAINS) and the presence of molecules previously reported as inhibitors of Mpro or PLpro to optimize resources and time in the discovery of new SARS-CoV-2 antivirals from plant-derived molecules.

Figure 1

Three-dimensional structures of the SARS-CoV-2 proteases Mpro (A) and PLpro (B). The structural domains and catalytic residues are highlighted.

Figure 2

(A) Percentage of molecules predicted to bind each target protease. (B) Percentage of articles reporting molecules as inhibitors of each target protease. (C) Percentage of molecules identified as inhibitors of the target proteases using molecular docking or molecular dynamics simulations (MD). (D) Distribution of articles per country. (E) Plants with more than two compounds proposed as a SARS-CoV-2 protease inhibitor.

Figure 3

Distribution of the molecular superclasses and classes across the 648 molecules using NPClassifier.

Figure 4

Structures of the top ten molecules more frequently reported in the studies analyzed. These molecules are predicted as potential inhibitors of Mpro and PLpro.

Figure 5

Top scaffolds identified using the Murcko algorithm in the 648 molecules. Only scaffolds found in more than 5 molecules are present.

Figure 6

Binding modes of baicalein (blue, PDB ID: 6M2N) and myricetin (white, PDB ID: 7DPP; salmon PDB ID: 7B3E) in the active site of SARS-CoV-2 Mpro.

Figure 7

Top 15 scaffolds representing the most abundant molecules in the 100 with high similarity (similarity is ≥0.75) to those with experimental evidence. The scaffolds were grouped according to flavone with and without sugar derivatives (yellow panel, including flavones, flavonols, isoflavones and diflavones), flavanone (green panel, including flavanonols), anthocyanins (blue panel), flavan-3-ols (red panel), anthraquinone (dark blue), steroids and triterpenoids (gray panel), and finally curcumin (brown panel).