Inhibition Potencies of Phytochemicals Derived from Sesame Against SARS-CoV-2 Main Protease: A Molecular Docking and Simulation Study

Kumar, Anuj; Mishra, Dwijesh Chandra; Angadi, U. B.; Yadav, Rashmi; Rai, Anil; Kumar, Dinesh

doi:10.3389/fchem.2021.744376

Cited by 34 publications

(30 citation statements)

References 125 publications

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“…The above finding may have just been verified by a recent in silico study using a computer-aided drug designing approach: Rifampicin was the most promising existing drug that could be repurposed for the treatment of COVID-19[ 39 ]. Moreover, using a comprehensive drug repurposing and molecular docking approach, prediction of potential inhibitors for RNA-dependent RNA polymerase of SARS-CoV-2 revealed that rifabutin could be an effective drug for COVID-19, having the lowest binding energy compared to the positive control remdesivir[ 40 ].…”

Section: In Silico Studies Indicate Possible Effectiveness O...mentioning

confidence: 83%

Rifampicin for COVID-19

Panayiotakopoulos¹,

Papadimitriou²

2022

WJV

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Vaccinations for coronavirus disease-2019 (COVID-19) have begun more than a year before, yet without specific treatments available. Rifampicin, critically important for human medicine (World Health Organization’s list of essential medicines), may prove pharmacologically effective for treatment and chemoprophylaxis of healthcare personnel and those at higher risk. It has been known since 1969 that rifampicin has a direct selective antiviral effect on viruses which have their own RNA polymerase (severe acute respiratory syndrome coronavirus 2), like the main mechanism of action of remdesivir. This involves inhibition of late viral protein synthesis, the virion assembly, and the viral polymerase itself. This antiviral effect is dependent on the administration route, with local application resulting in higher drug concentrations at the site of viral replication. This would suggest also trying lung administration of rifampicin by nebulization to increase the drug’s concentration at infection sites while minimizing systemic side effects. Recent in silico studies with a computer-aided approach, found rifampicin among the most promising existing drugs that could be repurposed for the treatment of COVID-19.

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Section: In Silico Studies Indicate Possible Effectiveness O...mentioning

confidence: 83%

Rifampicin for COVID-19

Panayiotakopoulos¹,

Papadimitriou²

2022

WJV

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“…The Open Babel toolbox ( O’Boyle et al, 2011 ) which is available in the PyRx package was utilized to convert these molecules into the PDBQT format. All four compounds were prepared by adding the polar hydrogens and Gasteiger charges as previously described in Kumar et al (2021) .…”

Section: Methodsmentioning

confidence: 99%

“…Eleven amino acid residues, namely, Thr24, Thr26, Asn119, Phe140, Gly143, Cys145, His163, His164, Glu166, Gln189, and Thr190, were used as the active sites of the receptor protein. These active site residues were considered based on the previous reports by Khan et al (2020) and Kumar et al (2021) . During the molecular docking process, the M pro was fixed, while the ligand molecules were flexible.…”

Section: Methodsmentioning

confidence: 99%

“…M pro consists of 306 amino acids yielding a molecular mass of 33,797 Da ( Khan et al, 2020 ). M pro is composed of three functional domains: domain I (8-101 aa), domain II (102-184 aa), and domain III (201-306 aa) ( Jin et al, 2020 ; Kumar et al, 2021 ). Based on structure topology, it has been well reported that an antiparallel ß -barrel structure is present in domains I and II.…”

Section: Introductionmentioning

confidence: 99%

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Potential of Natural Alkaloids From Jadwar (Delphinium denudatum) as Inhibitors Against Main Protease of COVID-19: A Molecular Modeling Approach

Kumar

Sharma

Richardson

et al. 2022

Front. Mol. Biosci.

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The ongoing pandemic coronavirus disease (COVID-19) caused by a novel corona virus, namely, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has had a major impact on global public health. COVID-19 cases continue to increase across the globe with high mortality rates in immunocompromised patients. There is still a pressing demand for drug discovery and vaccine development against this highly contagious disease. To design and develop antiviral drugs against COVID-19, the main protease (Mpro) has emerged as one of the important drug targets. In this context, the present work explored Jadwar (Delphinium denudatum)–derived natural alkaloids as potential inhibitors against Mpro of SARS-CoV-2 by employing a combination of molecular docking and molecular dynamic simulation–based methods. Molecular docking and interaction profile analysis revealed strong binding on the Mpro functional domain with four natural alkaloids viz. panicutine (−7.4 kcal/mol), vilmorrianone (−7.0 kcal/mol), denudatine (−6.0 kcal/mol), and condelphine (−5.9 kcal/mol). The molecular docking results evaluated by using the MD simulations on 200 nanoseconds confirmed highly stable interactions of these compounds with the Mpro. Additionally, mechanics/generalized Born/Poisson–Boltzmann surface area (MM/G/P/BSA) free energy calculations also affirmed the docking results. Natural alkaloids explored in the present study possess the essential drug-likeness properties, namely, absorption, distribution, metabolism, and excretion (ADME), and are in accordance with Lipinski’s rule of five. The results of this study suggest that these four bioactive molecules, namely, condelphine, denudatine, panicutine, and vilmorrianone, might be effective candidates against COVID-19 and can be further investigated using a number of experimental methods.

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“…Structure-based virtual screening (SBVS) of diverse ligand databases, many of them containing drug repurposing candidates and natural products, has been extensively applied to identify potential 3CL pro inhibitors (Wu C. et al, 2020;Chowdhury et al, 2020;Jukic et al, 2020;Meyer-Almes, 2020;Olubiyi et al, 2020;Selvaraj et al, 2020;Federico et al, 2021;Gogoi et al, 2021;Guedes et al, 2021;Kumar et al, 2021;Lokhande et al, 2021;Naik et al, 2021;Rajpoot et al, 2021;Rehman et al, 2021;Sisakht et al, 2021). In several cases, this approach has led to the successful identification of compounds displaying in vitro inhibitory activity against 3CL pro (Ghahremanpour et al, 2020;Gupta et al, 2020;Jin et al, 2020;Li et al, 2020;Alves et al, 2021;Banerjee et al, 2021;Gunther et al, 2021;Guo et al, 2021;Gupta et al, 2021;Hamdy et al, 2021;Pathak et al, 2021;Yang et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

A Computer-Aided Approach for the Discovery of D-Peptides as Inhibitors of SARS-CoV-2 Main Protease

González

Eberle

Willbold

et al. 2022

Front. Mol. Biosci.

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The SARS-CoV-2 main protease, also known as 3-chymotrypsin-like protease (3CLpro), is a cysteine protease responsible for the cleavage of viral polyproteins pp1a and pp1ab, at least, at eleven conserved sites, which leads to the formation of mature nonstructural proteins essential for the replication of the virus. Due to its essential role, numerous studies have been conducted so far, which have confirmed 3CLpro as an attractive drug target to combat Covid-19 and have reported a vast number of inhibitors and their co-crystal structures. Despite all the ongoing efforts, D-peptides, which possess key advantages over L-peptides as therapeutic agents, have not been explored as potential drug candidates against 3CLpro. The current work fills this gap by reporting an in silico approach for the discovery of D-peptides capable of inhibiting 3CLpro that involves structure-based virtual screening (SBVS) of an in-house library of D-tripeptides and D-tetrapeptides into the protease active site and subsequent rescoring steps, including Molecular Mechanics Generalized-Born Surface Area (MM-GBSA) free energy calculations and molecular dynamics (MD) simulations. In vitro enzymatic assays conducted for the four top-scoring D-tetrapeptides at 20 μM showed that all of them caused 55–85% inhibition of 3CLpro activity, thus highlighting the suitability of the devised approach. Overall, our results present a promising computational strategy to identify D-peptides capable of inhibiting 3CLpro, with broader application in problems involving protein inhibition.

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Inhibition Potencies of Phytochemicals Derived from Sesame Against SARS-CoV-2 Main Protease: A Molecular Docking and Simulation Study

Cited by 34 publications

References 125 publications

Rifampicin for COVID-19

Rifampicin for COVID-19

Potential of Natural Alkaloids From Jadwar (Delphinium denudatum) as Inhibitors Against Main Protease of COVID-19: A Molecular Modeling Approach

A Computer-Aided Approach for the Discovery of D-Peptides as Inhibitors of SARS-CoV-2 Main Protease

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