Reprofiling of approved drugs against SARS-CoV-2 main protease: an in-silico study

Kumar, Prateek; Bhardwaj, Taniya; Kumar, Ankur; Gehi, Bhuvaneshwari R.; Kapuganti, Shivani Krishna; Garg, Neha; Nath, Gopal; Giri, Rajanish

doi:10.1080/07391102.2020.1845976

Cited by 25 publications

(24 citation statements)

References 56 publications

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“…Furthermore, based on recent docking experiments, amikacin could be useful in the treatment of viral infections including COVID-19 [19]. Unfortunately, a substantial percentage of A. baumannii clinical isolates have acquired resistance to these antibiotics.…”

Section: Effect Of Ag 1+ On Aac(6 )-Ib-mediated Acetylation Of Amikacinmentioning

confidence: 99%

“…Amikacin and other aminoglycosides are important components of the armamentarium against A. baumannii and other bacterial infections [17,18]. Furthermore, based on recent docking experiments, amikacin could be useful in the treatment of viral infections including COVID-19 [19]. Unfortunately, a substantial percentage of A. baumannii clinical isolates have acquired resistance to these antibiotics.…”

Section: Introductionmentioning

confidence: 99%

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Aminoglycoside 6′-N-acetyltransferase Type Ib [AAC(6′)-Ib]-Mediated Aminoglycoside Resistance: Phenotypic Conversion to Susceptibility by Silver Ions

et al. 2020

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Clinical resistance to amikacin and other aminoglycosides is usually due to the enzymatic acetylation of the antimicrobial molecule. A ubiquitous resistance enzyme among Gram-negatives is the aminoglycoside 6′-N-acetyltransferase type Ib [AAC(6′)-Ib], which catalyzes acetylation using acetyl-CoA as a donor substrate. Therapies that combine the antibiotic and an inhibitor of the inactivation reaction could be an alternative to treat infections caused by resistant bacteria. We previously observed that metal ions such as Zn2+ or Cu2+ in complex with ionophores interfere with the AAC(6′)-Ib-mediated inactivation of aminoglycosides and reduced resistance to susceptibility levels. Ag1+ recently attracted attention as a potentiator of aminoglycosides′ action by mechanisms still in discussion. We found that silver acetate is also a robust inhibitor of the enzymatic acetylation mediated by AAC(6′)-Ib in vitro. This action seems to be independent of other mechanisms, like increased production of reactive oxygen species and enhanced membrane permeability, proposed to explain the potentiation of the antibiotic effect by silver ions. The addition of this compound to aac(6′)-Ib harboring Acinetobacter baumannii and Escherichia coli cultures resulted in a dramatic reduction of the resistance levels. Time-kill assays showed that the combination of silver acetate and amikacin was bactericidal and exhibited low cytotoxicity to HEK293 cells.

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Section: Effect Of Ag 1+ On Aac(6 )-Ib-mediated Acetylation Of Amikacinmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Aminoglycoside 6′-N-acetyltransferase Type Ib [AAC(6′)-Ib]-Mediated Aminoglycoside Resistance: Phenotypic Conversion to Susceptibility by Silver Ions

et al. 2020

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“…The docking of MTX against the simulated structure of NSP1-CTR was performed and the molecular interactions between the complex were analyzed using the Glide XP (Extra Precision) program in the Schrodinger suite 26 . The parameters for protein structure and ligand preparation are kept as previously reported 27 . Grid coordinates were set as 28.0, 24.0, and 33.18 Å for X, Y, and Z, respectively.…”

Section: Methodsmentioning

confidence: 99%

Mitoxantrone dihydrochloride, an FDA approved drug, binds with SARS-CoV-2 NSP1 C-terminal

Kumar

Bhardwaj

Giri

2021

Preprint

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One of the major virulence factors of SARS-CoV-2, NSP1, is a vital drug target due to its role in host immune evasion through multiple pathways. NSP1 protein is associated with inhibiting host mRNA translation by binding to the small subunit of ribosome through its C-terminal region. Previously, we have shown the structural dynamics of NSP1 C-terminal region (NSP1-CTR) in different physiological environments. So, it would be very interesting to investigate the druggable compounds that could bind with NSP1-CTR. Here, in this article, we have performed the different spectroscopic technique-based binding assays of an anticancer drug Mitoxantrone dihydrochloride (MTX) against the NSP1-CTR. We have also performed molecular docking followed by computational simulations with two different forcefields up to one microsecond. Overall, our results have suggested good binding between NSP1-CTR and MTX and may have implications in developing therapeutic strategies targeting NSP1 protein of SARS-CoV-2.

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“…These SARS-CoV-2 NSPs are highly similar to their SARS-CoV equivalents (93.29% to 100% homology) [ 75 ] and are expressed from the cleavage of two polyproteins translated by the host ribosomes from the 5ʹ portion of the viral genome [ 76 ]. Their maturation is carried out by the two viral proteases NSP3 (papain-like proteinase) and NSP5 (3-chymotrypsin-like proteinase) [ 77 , 78 ] that are also promising target for drug development and existing marine natural compounds [ 79 ]. Moreover SARS-CoV-2 NSP3 macrodomain was shown to have a stronger interaction with ADP-ribose by docking experiment suggesting also a role in the host antiviral response [ 8 ].…”

Section: Structure and Function Of The Sars-cov-2 Rna Polymerase: Thementioning

confidence: 99%

Analysis of the SARS-CoV-2-host protein interaction network reveals new biology and drug candidates: focus on the spike surface glycoprotein and RNA polymerase

Sokullu

Pinard

Gauthier

et al. 2021

Expert Opinion on Drug Discovery

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Introduction : The COVID-19 pandemic originated from the emergence of anovel coronavirus, SARS-CoV-2, which has been intensively studied since its discovery in order to generate the knowledge necessary to accelerate the development of vaccines and antivirals. Of note, many researchers believe there is great potential in systematically identifying host interactors of viral factors already targeted by existing drugs. Areas Covered : Herein, the authors discuss in detail the only available large-scale systematic study of the SARS-CoV-2-host protein–protein interaction network. More specifically, the authors review the literature on two key SARS-CoV-2 drug targets, the Spike surface glycoprotein, and the RNA polymerase. The authors also provide the reader with their expert opinion and future perspectives. Expert opinion : Interactions made by viral proteins with host factors reveal key functions that are likely usurped by the virus and, as aconsequence, points to known drugs that can be repurposed to fight viral infection and collateral damages that can exacerbate various disease conditions in COVID-19.

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Reprofiling of approved drugs against SARS-CoV-2 main protease: an in-silico study

Cited by 25 publications

References 56 publications

Aminoglycoside 6′-N-acetyltransferase Type Ib [AAC(6′)-Ib]-Mediated Aminoglycoside Resistance: Phenotypic Conversion to Susceptibility by Silver Ions

Aminoglycoside 6′-N-acetyltransferase Type Ib [AAC(6′)-Ib]-Mediated Aminoglycoside Resistance: Phenotypic Conversion to Susceptibility by Silver Ions

Mitoxantrone dihydrochloride, an FDA approved drug, binds with SARS-CoV-2 NSP1 C-terminal

Analysis of the SARS-CoV-2-host protein interaction network reveals new biology and drug candidates: focus on the spike surface glycoprotein and RNA polymerase

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