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

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.