Comprehensive virtual screening of 4.8 k flavonoids reveals novel insights into allosteric inhibition of SARS-CoV-2 MPRO

Abstract

SARS-CoV-2 main protease is a common target for inhibition assays due to its high conservation among coronaviruses. Since flavonoids show antiviral activity, several in silico works have proposed them as potential SARS-CoV-2 main protease inhibitors. Nonetheless, there is reason to doubt certain results given the lack of consideration for flavonoid promiscuity or main protease plasticity, usage of short library sizes, absence of control molecules and/or the limitation of the methodology to a single target site. Here, we report a virtual screening study where dorsilurin E, euchrenone a11, sanggenol O and CHEMBL2171598 are proposed to inhibit main protease through different pathways. Remarkably, novel structural mechanisms were observed after sanggenol O and CHEMBL2171598 bound to experimentally proven allosteric sites. The former drastically affected the active site, while the latter triggered a hinge movement which has been previously reported for an inactive SARS-CoV main protease mutant. The use of a curated database of 4.8 k flavonoids, combining two well-known docking software (AutoDock Vina and AutoDock4.2), molecular dynamics and MMPBSA, guaranteed an adequate analysis and robust interpretation. These criteria can be considered for future screening campaigns against SARS-CoV-2 main protease.

Identifying RO9021 as a Potential Inhibitor of PknG fromMycobacterium tuberculosis: Combinative Computational and In Vitro Studies

“…This script was successfully used in the previous work. 50 The evaluation was carried out with 100 ps of resolution. The frequency of each ligand’s interactions per protein residue was expressed as a percentage of the total interactions established by the ligand in stacked bar plots.…”

Identification of Aloe-derived natural products as prospective lead scaffolds for SARS-CoV-2 main protease (Mpro) inhibitors

“…1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 17 , 18 , 19 , 20 , 21 , 22 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 63 , 64 .…”

Commercially Available Flavonols Are Better SARS-CoV-2 Inhibitors than Isoflavone and Flavones

“…Coronavirus disease 2019 (COVID- 19) is the most recent global pandemic of the 21st century, causing over 530 million confirmed cases and 6.29 million deaths worldwide from December 2020 until May 2022 [1]. Despite the fast development of vaccines and approved drugs by the U.S. Food and Drug Administration (FDA), e.g., remdesivir and baricitinib [2], severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is still circulating due to variants of concern (VoC) that escape the humoral immune response; antiviral resistance might occur in the future [3][4][5][6].…”

“…In this regard, a class of natural polyphenols known as flavonoids, found in different amounts in plants, is being considered for the treatment of different diseases [ 15 , 16 , 17 ]. Flavonoids gained particular attention as potential anti-SARS-CoV-2 agents due to their ability to target some essential viral proteins in their entry and replication steps [ 17 , 18 , 19 , 20 ]. However, most of these reports are based on in silico screening or viral growth assessed in Vero-E6- and A549-cells, which are not considered ideal cellular models for SARS-CoV-2 infection [ 21 , 22 ]; thus, a better characterization of flavonoids for COVID-19 is still needed.…”