Inhibitory activity of hydroxychloroquine on COVID-19 main protease: An insight from MD-simulation studies

Baildya, Nabajyoti; Ghosh, Narendra Nath; Chattopadhyay, Asoke P.

doi:10.1016/j.molstruc.2020.128595

Cited by 71 publications

(56 citation statements)

References 22 publications

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“…Recently few studies have indicated Spike glycoprotein, RNA-dependent RNA polymerase, Chimeric Receptor-binding domain, Main protease, Non-structural Protein 3, Non-structural Protein 9, ADP-ribose-1 monophosphatase and NTD-N protein as the drug target of CQ and HCQ (Baildya et al., 2020 ; Mukherjee et al., 2020 ; Nimgampalle et al., 2020 ). However, in present study, we studied PLpro drug target and aimed to characterise the binding mode, binding affinities and key amino acid residues in CQ and HCQ binding to PLpro.…”

Section: Resultsmentioning

confidence: 99%

“…Recent molecular docking and simulations studies have revealed the binding mechanism and stabilisation of HCQ with SARS-CoV-2 main protease (Mpro) through non-covalent interactions (Mukherjee et al., 2020 ). Another similar molecular docking study of HCQ against main protease (Mpro) have suggested that compound binding is facilitated by the conformational and rotational changes (Baildya et al., 2020 ). Recently, Nimgampalle & co-workers have also performed molecular docking studies of CQ, HCQ and its derivatives against multiple SAR-CoV-2 proteins (Spike glycoprotein, RNA-dependent RNA polymerase, Chimeric Receptor-binding domain, Main protease, Non-structural Protein 3, Non-structural Protein 9, ADP-ribose-1 monophosphatase) (Nimgampalle et al., 2020 ).…”

Section: Introductionmentioning

confidence: 99%

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Computational investigation of binding of chloroquinone and hydroxychloroquinone against PLPro of SARS-CoV-2

Patel

Athar

Jha

2020

Journal of Biomolecular Structure and Dynamics

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Novel coronavirus SARS-CoV-2 has infected 18 million people with 700,000þ mortalities worldwide and this deadly numeric figure is rapidly rising. With very few success stories, the therapeutic targeting of this epidemic has been mainly attributed to main protease (Mpro), whilst Papain-like proteases (PLpro) also plays a vital role in the processing of replicase polyprotein. Multifunctional roles of PLpro such as viral polypeptide cleavage, de-ISGlyation and immune suppression have made it a promising drug target for therapeutic interventions. Whilst there have been a number of studies and others are ongoing on repurposing and new-small molecule screening, albeit previously FDA approved drugs viz. Chloroquine (CQ) and Hydroxychloroquine (HCQ) have only been found effective against this pandemic. Inspired by this fact, we have carried out molecular docking and dynamics simulation studies of FDA approved CQ and HCQ against SARS-CoV-2 PLpro. The end aim is to characterise the binding mode of CQ and HCQ and identify the key amino acid residues involved in the mechanism of action. Further, molecular dynamics simulations (MDS) were carried out with the docked complex to search for the conformational space and for understanding the integrity of binding mode. We showed that the CQ and HCQ can bind with better binding affinity with PLpro as compared to reference known PLpro inhibitor. Based on the presented findings, it can be anticipated that the SARS-CoV-2 PLpro may act as molecular target of CQ and HCQ, and can be projected for further exploration to design potent inhibitors of SARS-CoV-2 PLpro in the near future.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Computational investigation of binding of chloroquinone and hydroxychloroquinone against PLPro of SARS-CoV-2

Patel

Athar

Jha

2020

Journal of Biomolecular Structure and Dynamics

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“…Although several drugs (chloroquine, hydroxy-chloroquine, remdesivir etc.) are recommended against COVID-19, many adverse effects of these have also been reported [ 7 , 8 ]. These drug molecules target different entities in the virus or its binding with the host cell.…”

Section: Introductionmentioning

confidence: 99%

Screening of potential drug from Azadirachta Indica (Neem) extracts for SARS-CoV-2: An insight from molecular docking and MD-simulation studies

Baildya

Khan

Ghosh

et al. 2021

Journal of Molecular Structure

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Highlights 19 compounds from Neem extract tested against 7 standard anti-COVID drugs for action on PLpro of latter All 19 NEEM molecules show better docking, ADME results vis-a-vis standard drugs Among the 19, desacetylgedunin (DCG) gives highest docking score with PLpro MD simulation of shows binding with DCG induces large structural change on PLpro

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“…Chloroquine and hydroxychloroquine act as weak bases which can have several intracellular effects, including affecting intracellular traffic and disrupting enzymes [ 13 ]. Studies of molecular docking and mechanic molecular simulation of Baildya et al suggest that hydroxychloroquine could have a considerable effect on SARS-COV-2 main protease, which could have a significant inhibitory effect on it [ 14 ]. Unfortunately these two drugs have toxic effects and their use in high doses can create major risks for patients [ 14 , 15 ]; that is why the use of these drugs to treat covid-19 is not recommended by World Health Organization (WHO) [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

Assessment of effective imidazole derivatives against SARS-CoV-2 main protease through computational approach

et al. 2020

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Because of the fast increase in deaths due to Corona Viral Infection in majority region in the world, the detection of drugs potent of this infection is a major need. With this idea, docking study was executed on eighteen imidazole derivatives based on 7-chloro-4-aminoquinoline against novel Coronavirus (SARS-CoV-2). In this study, we carried out a docking study of these molecules in the active site of SARS-CoV-2 main protease. The result indicate that Molecules N° 3, 7 and 14 have more binding energy with SARS-CoV-2 main protease recently crystallized (pdb code 6LU7 ) in comparison with the other imidazole derivatives and the two drug; Chloroquine and hydroxychloroquine. Because of the best energy of interaction, these three molecules could have the most potential antiviral treatment of COVID-19 than the other studied compounds. The structures with best affinity in the binding site of the protease have more than 3 cycles and electronegative atoms in the structure. This may increase the binding affinity of these molecules because of formation of π-bonds, halogen interactions and/or Hydrogen bond interactions between compounds and the enzyme. So, compounds with more cycles and electronegative atoms could have a potent inhibition of SARS-CoV-2 main protease.

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Inhibitory activity of hydroxychloroquine on COVID-19 main protease: An insight from MD-simulation studies

Cited by 71 publications

References 22 publications

Computational investigation of binding of chloroquinone and hydroxychloroquinone against PLPro of SARS-CoV-2

Computational investigation of binding of chloroquinone and hydroxychloroquinone against PLPro of SARS-CoV-2

Screening of potential drug from Azadirachta Indica (Neem) extracts for SARS-CoV-2: An insight from molecular docking and MD-simulation studies

Assessment of effective imidazole derivatives against SARS-CoV-2 main protease through computational approach

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