Unravelling lead antiviral phytochemicals for the inhibition of SARS-CoV-2 Mpro enzyme through in silico approach

Gurung, Arun Bahadur; Ali, Mohammad Ajmal; Lee, Dong Kun; Farah, Mohammad Abul; Al-Anazi, Khalid Mashay

doi:10.1016/j.lfs.2020.117831

Cited by 120 publications

(113 citation statements)

References 35 publications

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“…These two crystal structures also laid the basis toward the structure-based drug design against Mpro. Many small molecules are being proposed as effective SARS CoV-2 Mpro inhibitor (Bhardwaj et al, 2020 ; Das et al, 2020 ; Ghosh et al, 2020a , 2020b ; Gorla et al, 2020 ; Gurung et al, 2020 ; Joshi et al, 2020 a, 2020 b; Mazzini et al, 2020 ). Several anti-HIV drugs (darunavir, lopinavir, atazanavir, etc.)…”

Section: Resultsmentioning

confidence: 99%

“…Even, in blind docking, the docked conformation having the lowest binding energy depicted that dexamethasone and betamethasone have non-covalent interaction (other than H-bond interaction) with these two important amino acid residues of Mpro ( Supplementary Figure S1 ). In fact, there are many reports available in the literature where investigators noticed the formation of non-covalent bonds (other than H-bond) including alkyl bond(s) between compounds and residues of catalytic site (His41 and Cys145) of the Mpro (Bhardwaj et al, 2020 ; Das et al, 2020 ; Gurung et al, 2020 ; Islam et al, 2020 ; Joshi et al, 2020 ; Odhar et al, 2020 ). We believe that the availability and/or accessibility of Cys145 as well as His41 of Mpro may be ceased down due to the formation of alkyl bond(s) between compounds and these two residues of Mpro and such alterations possibly can inhibit its (Mpro) catalytic activity.…”

Section: Resultsmentioning

confidence: 99%

“…Thus, it can be concluded that betamethasone and dexamethasone may possibly inhibit the proteolytic activity of Mpro and may potentially be repurposed to treat patients with COVID-19. We also computed the inhibition constant ( k i ) so as to get the idea about the inhibition potency of dexamethasone and betamethasone toward Mpro (Gurung et al, 2020 ). Inhibition constant ( k i ) was estimated using the following equation: where Δ G is the binding energy in kcal/mol, R is the universal gas constant (1.987 cal K −1 mol −1 ) and T is the temperature (298 K).…”

Section: Resultsmentioning

confidence: 99%

“…Thus, they have revealed, both the structures of substrate-binding site of Mpro as well as structure-based approach for designing potential drug molecules against COVID-19. Based on these, natural products and phytochemicals have been studied to find an effective inhibitor of Mpro (Bhardwaj et al, 2020 ; Das et al, 2020 ; Ghosh et al, 2020a , 2020b ; Gorla et al, 2020 ; Gurung et al, 2020 ; Joshi et al, 2020a , 2020b ; Mazzini et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

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Potential therapeutic use of corticosteroids as SARS CoV-2 main protease inhibitors: a computational study

Ghosh

Chakraborty

Biswas

et al. 2020

Journal of Biomolecular Structure and Dynamics

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The outbreak of COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS CoV-2), represents a pandemic threat to global public health. To date, ∼530,000 people died of this disease worldwide. Presently, researchers/clinicians are adopting the drug repurposing strategy to combat this disease. It has also been observed that some repurposed anti-viral drugs may serve as potent inhibitors of SARS CoV-2 Mpro, a key component of viral replication. Apart from these anti-viral drugs, recently dexamethasone (an important corticosteroid) is effectively used to treat COVID-19 patients. However, the mechanism behind the mode of its action is not so clear. Additionally, the effect of other well-known corticosteroids to control this disease by inhibiting the proteolytic activity of Mpro is ambiguous. In this study, we have adopted computational approaches to understand these aspects. Six well-known corticosteroids (cortisone, hydrocortisone, prednisolone, methylprednisolone, betamethasone and dexamethasone) and two repurposed drugs (darunavir and lopinavir) against COVID-19 were subjected for molecular docking studies. Two of them (betamethasone and dexamethasone) were selected by comparing their binding affinities with selected repurposed drugs toward Mpro. Betamethasone and dexamethasone interacted with both the catalytic residues of Mpro (His41 and Cys145). Molecular dynamics studies further revealed that these two Mpro-corticosteroid complexes are more stable, experience less conformational fluctuations and more compact than Mpro-darunavir/lopinavir complexes. These findings were additionally validated by MM-GBSA analysis. This study provides corroboration for execution of anti-COVID-19 activity of dexamethasone. Our study also emphasizes on the use of another important corticosteroid (betamethasone) as potential therapeutic agent for COVID-19 treatment.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Potential therapeutic use of corticosteroids as SARS CoV-2 main protease inhibitors: a computational study

Ghosh

Chakraborty

Biswas

et al. 2020

Journal of Biomolecular Structure and Dynamics

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“…Currently, scientific community are largely focused in the screening of – (i) FDA-approved drug databases, (ii) clinical trials molecules and/or (iii) previously reported coronavirus inhibitors 9 . In silico virtual screening (VS) techniques are proficient to explore CoV protease inhibitors 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 . Yu and co-workers 40 reported the computational screening and findings with regard to potential binding luteolin and other natural compounds against Mpro.…”

Section: Search Of Protease Inhibitors Against Covid-19mentioning

confidence: 99%

Protease targeted COVID-19 drug discovery and its challenges: Insight into viral main protease (Mpro) and papain-like protease (PLpro) inhibitors

Amin

Banerjee

Ghosh

et al. 2021

Bioorganic & Medicinal Chemistry

137

102

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In silico investigations of the multi‐targeted antiviral potential of small molecule phytochemicals of Nelumbo nucifera Gaertn. seed extracts against SARS‐CoV‐2 for therapeutics of COVID‐19

et al. 2023

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The therapeutics of COVID‐2 was significantly obtained from nutraceutical approaches based on traditional knowledges and long practices. The current study was aimed to investigate antiviral potential of small molecule phytochemicals of seeds of Nelumbo nucifera against the SARS‐CoV‐2 proteins. GC–MS analysis resulted in identifying 12 dominating small molecule phytocompounds from the seed extracts of the N. nucifera. Further, we selected RNA‐dependent RNA polymerases (RdRps), spike protein, and M protein of SARS‐CoV‐2 as antiviral targets and performed in silico analyses, including protein docking (ligands), ADMET predictions, and molecular dynamics (MD). The studies revealed that the molecular interactions (protein–ligands) of three target proteins, namely, RdRp, spike protein, and M‐protein, have significant binding energies with three different substrates, namely, 1‐(8′‐methylquinolin‐2′‐yl)‐2,3,4‐tri(methoxycarbonyl)‐6‐(1″,2″‐di(methoxycarbonyl)vinyloxy)benzene (binding energy −5.84 kcal/mol) 2(1H)‐pyrimidinone, 5‐chloro‐4,6‐diphenyl (binding energy −6.60 kcal/mol), and nickel, [2,8,12,18‐tetraethyl‐3,7,13,17‐tetramethyl‐21H,23H‐porphinato(2‐)‐N21,N22,N23,N24]‐, (SP‐4‐1) (binding energy −7.02 kcal/mol), respectively. The ADMET predictions show significant pharmacokinetic profiles of the druggability of the three compounds of different targets. The pharmacokinetic activities critical to predicting stages of the drug development process are gastrointestinal absorption and brain access. The MD simulation showed that the systems were stable, referring to them as a potentially effective treatment for SARS‐CoV‐2. Therefore, a possible initiative has been taken to evaluate three potent small molecules of antiviral phytocompounds made from typically edible N. nucifera seed to support the nutraceutical approach to COVID‐19 therapeutics.

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Unravelling lead antiviral phytochemicals for the inhibition of SARS-CoV-2 Mpro enzyme through in silico approach

Cited by 120 publications

References 35 publications

Potential therapeutic use of corticosteroids as SARS CoV-2 main protease inhibitors: a computational study

Potential therapeutic use of corticosteroids as SARS CoV-2 main protease inhibitors: a computational study

Protease targeted COVID-19 drug discovery and its challenges: Insight into viral main protease (Mpro) and papain-like protease (PLpro) inhibitors

In silico investigations of the multi‐targeted antiviral potential of small molecule phytochemicals of Nelumbo nucifera Gaertn. seed extracts against SARS‐CoV‐2 for therapeutics of COVID‐19

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