Flavonoid glycosides and their putative human metabolites as potential inhibitors of the SARS-CoV-2 main protease (Mpro) and RNA-dependent RNA polymerase (RdRp)

Abstract

BACKGROUND Since the World Health Organization (WHO) declared Coronavirus disease 2019 (COVID-19) to be a pandemic infection, important severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) non-structural proteins (nsp) have been analysed as promising targets in virtual screening approaches. Among these proteins, 3-chymotrypsin-like cysteine protease (3CLpro), also named main protease, and the RNA-dependent RNA polymerase (RdRp), have been identified as fundamental targets due to its importance in the viral replication stages. OBJECTIVES To investigate, in silico, two of the most abundant flavonoid glycosides from Dysphania ambrosioides; a medicinal plant found in many regions of the world, along with some of the putative derivatives of these flavonoid glycosides in the human organism as potential inhibitors of the SARS-CoV-2 3CLpro and RdRp. METHODS Using a molecular docking approach, the interactions and the binding affinity with SARS-CoV-2 3CLpro and RdRp were predicted for quercetin-3-O-rutinoside (rutin), kaempferol-3-O-rutinoside (nicotiflorin) and some of their glucuronide and sulfate derivatives. FINDINGS Docking analysis, based on the crystal structure of 3CLpro and RdRp, indicated rutin, nicotiflorin, and their glucuronide and sulfate derivatives as potential inhibitors for both proteins. Also, the importance of the hydrogen bond and π-based interactions was evidenced for the presumed active sites. MAIN CONCLUSIONS Overall, these results suggest that both flavonoid glycosides and their putative human metabolites can play a key role as inhibitors of the SARS-CoV-2 3CLpro and RdRp. Obviously, further researches, mainly in vitro and in vivo experiments, are necessary to certify the docking results reported here, as well as the adequate application of these substances. Furthermore, it is necessary to investigate the risks of D. ambrosioides as a phytomedicine for use against COVID-19.

How glycobiology can help us treat and beat the COVID-19 pandemic

“…The identification of potential inhibitors of SARS-CoV-2 main protease using molecular docking studies revealed flavonoid glycosides as candidate molecules ( 98 ). Flavonoid glycosides are polyphenolic structures with covalent linkage of sugars, and Hesperidin, Rutin and Quercitrin were identified as ligands of SARS-CoV-2 main protease, RNA-dependent RNA polymerase and S glycoprotein RBD ( 84 , 99 , 100 , 101 , 102 ) ( Table 1 and Figure 5 ). These repurposed FDA-approved drugs could protect against SARS-CoV-2 infection, where an important endothelial dysfunction probably associated to systemic complications is produced ( 103 ).…”

Reappraisal of Dietary Phytochemicals for Coronavirus Infection: Focus on Hesperidin and Quercetin

“…Da Silva et al [63] have expanded the search for molecules interacting with Mpro to a series of flavonoid glycosides using a molecular docking approach. The interactions and binding affinity with the protease by quercetin and even more by its glycosidic derivatives quercetin-3-O-rutinoside (rutin), quercetin-3-O-glucuronide, quercetin-3′-O-sulphate, quercetin-7-O-glucuronide, quercetin-7-O-sulfate were thus predicted.…”

“…Metabolites conjugated with the methyl, glucuronate and sulphate groups are the predominant forms present in plasma [64][65][66]. Quercetin has also been indicated as one of the substances capable of binding and thus inhibiting RNAdependent RNA polymerase, an essential enzyme in the replication of viral RNA in the host cell [63].…”

Repositioning microbial biotechnology against COVID‐19: the case of microbial production of flavonoids

“…Most of the computational docking studies focused on SARS‐CoV‐2 3CL pro as drug target (Chen et al ., 2020; Fischer et al ., 2020; Gao et al ., 2020; Islam et al ., 2020; Rasool et al ., 2020; Vijayakumar et al ., 2020; Da Silva et al ., 2020; Zhang et al ., 2020c, for preprints see SI2), also due to its central role in the viral life cycle (Fig. 1).…”

“…However, several flavonoids putatively active against SARS‐CoV 3CL pro or the spike protein were observed to have good binding values to one or more of the lesser studied drug targets as well. These flavonoids include baicalin, with good binding values to PL pro and nsp9 (Wu et al ., 2020) and hesperidin to nsp7_8 and the E‐channel (Wu et al ., 2020), rutin to RdRP (Da Silva et al ., 2020) plus some observations from preprints (SI2). In addition to the docking/molecular dynamics, two network analyses on SARS‐CoV‐2 drug finding were performed.…”