Molecules inhibit the enzyme activity of 3-chymotrypsin-like cysteine protease of SARS-CoV-2 virus: the experimental and theory studies

Abstract

SummarySARS-CoV-2 has emerged as a world public health threat. Herein, we report that the clinical approved auranofin could perfectly inhibit the activity of 3-chymotrypsin-like cysteine protease (Mpro or 3CLpro) of SARS-CoV-2. Gold cluster could significantly inhibit 3CLpro of SARS-COV-2. Phenyl isothiocyanate and Vitamin K3 could well suppress the activity of 3CLpro. For Mpro inhibition, IC50 of auranofin, Vitamin K3, phenyl isothiocyanate, gold cluster are about 0.51μM, 7.96μM, 10.13μM, 1.61μM, respectively. These compounds may be with potentials for treatment SARS-CoV-2 virus replication. Especially for FDA approved auranofin, it is an anti-inflammation drug in clinic, thus it may with strong potential to inhibit virus replication and suppress the inflammation damage in COVID-19 patients. Gold cluster is with better safety index and well anti-inflammation in vitro/vivo, therefore it is with potential to inhibit virus replication and suppress the inflammation damage caused by COVID-19 virus. As Au(I) ion is active metabolism specie derived from gold compounds or gold clusters in vivo, further computational studies revealed Au ion could tightly bind thiol group of Cys145 residue of 3CLpro thus inhibit enzyme activity. Also, phenyl isothiocyanate and Vitamin K3 may interact with thiol group of Cys145 via Michael addition reaction, molecular dynamic (MD) theory studied are applied to confirmed these small molecules are stable in the pocket and inhibit Mpro activity.

The repurposed drugs suramin and quinacrine inhibit cooperativelyin vitroSARS-CoV-2 3CLpro

“…The IC 50 values of both molecules are in a concentration range with other repurposed drug molecules, which also demonstrate inhibitory effect against SARS-CoV-2 3CL pro , for example; boceprevir has an IC 50 value of 4.14 μM (Ma et al, 2020), menadione presents IC 50 value of 7.9 μM (He et al, 2020) and disulfiram has an IC 50 of 9.35 μM (Jin et al, 2020).…”

“…Similar studies addressed the use of established drugs against SARS-CoV-2 (e.g. Boceprevir, Menadione and Disulfiram) (Ma et al, 2020; He et al, 2020; Jin et al, 2020). (Table 5) .…”

“…boceprevir has an IC50 value of 4.14 µM (Ma et al, 2020), menadione presents IC50 value of 7.9 µM (He et al, 2020) and disulfiram has an IC50 of 9.35 µM (Jin et al, 2020).…”

Propolis, Bee Honey, and Their Components Protect against Coronavirus Disease 2019 (COVID-19): A Review of In Silico, In Vitro, and Clinical Studies

“…Given that alterations in NSPs such as 3CLpro/Mpro, PLpro, and RdRp interfere with viral replication and threaten viral survival [ 1 , 47 , 87 ], several studies have examined the interaction of flavonoids in propolis and honey with these key viral enzymes [ 25 , 42 , 47 , 51 , 86 ]. Preliminary results pinpoint an inhibitory activity of flavonoids against NSPs of SARS-CoV-2 [ 25 , 42 , 47 , 51 ].…”

Identification of Vitamin K3 and its analogues as covalent inhibitors of SARS-CoV-2 3CLpro

“…In addition, Vitamin K3 exhibited a spectrum of anticancer activities and effects against various cancer cells [ [26] , [27] , [28] ]. Recent research has also found that Vitamin K3 can inhibit the activity of SARS-CoV-2 3CL pro and serve as a potential lead molecule for further antiviral studies to combat COVID-19 [ 29 ]. However, the mechanism of action of Vitamin K3 and the binding mode with SARS-CoV-2 3CL pro remain largely unknown.…”