Prediction of the SARS-CoV-2 (2019-nCoV) 3C-like protease (3CLpro) structure: virtual screening reveals velpatasvir, ledipasvir, and other drug repurposing candidates

Chen, Yu Wai; Yiu, Chin-Pang; Wong, Kwok Yin

doi:10.12688/f1000research.22457.2

Cited by 380 publications

(218 citation statements)

References 34 publications

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“…Comparative analysis of the affinity tendency observed for three of the 12 evaluated compounds previously reported by Farag et al (Darunavir > rosuvastatin > saquinavir) [8], Chen et al (ledipasvir > velpatasvir) [9], Adem et al (hesperidin > rutin > diosmin) [35], and Kumar et al (tipranavir > raltegravir) [10] revealed discrepancies when compared with our findings. These observations highlight the degree to which the computational strategy employed to identify potential inhibitors of SARS-CoV M pro impacted affinity tendency, and underscored the utility of combining docking, MD simulations and end-point binding free energy methods.…”

Section: Free Energy Of Bindingcontrasting

confidence: 99%

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Identification of saquinavir as a potent inhibitor of dimeric SARS-CoV2 main protease through MM/GBSA

Bello

Alberto

Balbuena-Rebolledo

2020

Preprint

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Among targets selected for studies aimed to identify potential inhibitors against COVID-19, SARS-CoV2 main proteinase (Mpro) is highlighted. Mpro is indispensable for virus replication, and is a promising target of potential inhibitors of COVID-19. Recently, monomeric SARS-CoV2 Mpro, drug repurposing and docking methods have facilitated the identification of several potential inhibitors. Results were refined through the assessment of dimeric SARS-CoV2 Mpro, which represents the functional state of enzyme. Docking and molecular dynamics (MD) simulations combined with molecular mechanics/generalized Born surface area (MM/GBSA) studies indicated that dimeric Mpro most significantly impacts binding affinity tendency compared with the monomeric state, which suggesting that dimeric state is most useful when performing studies aimed to identify drugs targeting Mpro. In this study, we extend previous research by performing docking and MD simulation studies coupled with an MM/GBSA approach to assess binding of dimeric SARS-CoV2 Mpro to 12 FDA-approved drugs (darunavir, indinavir, saquinavir, tipranavir, diosmin, hesperidin, rutin, raltegravir, velpatasvir, ledipasvir, rosuvastatin and bortezomib), which were identified as the best candidates for treatment of COVID-19 in some previous dockings studies involving monomeric SARS-CoV2 Mpro. This analysis identified saquinavir as a potent inhibitor of dimeric SARS-CoV2 Mpro, therefore, the compound may have clinical utility against COVID-19.

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Section: Free Energy Of Bindingcontrasting

confidence: 99%

“…in previous studies that virtually screened candidates targeting monomeric SARS-CoV2 M pro[8][9][10][11]. Of the 12 FDA approved drugs identified, darunavir, indinavir, saquinavir and tipranavir are HIV protease inhibitors, and…”

mentioning

confidence: 99%

Identification of saquinavir as a potent inhibitor of dimeric SARS-CoV2 main protease through MM/GBSA

Bello

Alberto

Balbuena-Rebolledo

2020

Preprint

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“…Accordingly, active genomic surveillance and close monitoring of the genomic sequence dynamics of SARS-CoV-2 is urgently required to: a) trace the pattern of geographic spread of the virus during the ongoing pandemic 10,11 ; b) ensure the effectiveness of vaccines and immune-based diagnostic or therapeutic interventions currently in use or under investigation 9 ; and c) identify putative therapeutic targets. [12][13][14] Geographic, gender, and age discrepancy of COVID-19 disease outcome have been reported by several studies. [15][16][17][18] Whether this correlates to SARS-CoV-2 genomic variation is still unclear.…”

Section: Introductionmentioning

confidence: 94%

Global dynamics of SARS-CoV-2 clades and their relation to COVID-19 epidemiology

Hamed

Elkhatib

Khairallah

et al. 2020

Preprint

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Expansion of COVID-19 worldwide increases interest in unraveling genomic variations of novel SARS-CoV-2 virus. Metadata of 60,703 SARS-CoV-2 genomes submitted to GISAID database were analyzed with respect to genomic clades and their geographic, age, and gender distributions. Clade GR was the most frequently identified followed by G and GH. Chronological analysis revealed expansion in SARS-CoV-2 clades with D614Gmutations indicating adaptation-driven evolution. Of them, clade GH showed a slight regression. GR, GH and L clades prevail in countries with higher deaths. GR clade showed higher prevalence among severe/deceased patients. Metadata analysis showed higher (p > 0.05) prevalence of severe/deceased cases among males than females and predominance of GR clade in female and children patients. Furthermore, severe disease/death was more prevalent (p < 0.05) in elderly than in adults/children. These findings uniquely provide an evidence-based evolution of SARS-CoV-2 leading to altered infectivity, virulence, and mortality.

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“…Coronaviruses genome is a single-stranded positive-sense RNA (+ssRNA) molecule with genomic size ranges between 27-32 kbp which contains at least six open reading frames (ORFs) [11][12][13]. The rst ORFs (ORF1a/b) encodes a polyprotein1a,b (pp1a, pp1b) while other ORFs are located on 3′ end encodes at least four structural proteins: envelop glycoprotein spike (S), responsible for recognizing host cell receptors, Membrane (M) proteins, responsible for shaping the virions, the Envelope (E) proteins, responsible for virions assembly and release and the Nucleocapsid (N) proteins are involved in packaging the RNA genome and in the virions and play roles in pathogenicity as an interferon (IFN) inhibitor [14,15]. In addition to the four main structural proteins, there are structural and accessory proteins that are species-speci c, such as HE protein, 3a/b protein, and 4a/b protein.…”

Section: Introductionmentioning

confidence: 99%

The first report of the most important sequential differences between COVID-19 and MERS viruses by attribute weighting models, the importance of Nucleocapsid (N) protein

Ebrahimi

Novikov

Ebrahimie

et al. 2020

Preprint

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COVID-19 and the Middle East respiratory syndrome-related coronavirus (MERS) viruses are from coronaviridae family; the former became a pandemic while the latter confined to a limited region. Their pathogenicity and infection rates are also different; the high mortality rate for MERS with low spreading capability. To investigate the possible structural changes at RNA sequences of both virus, 1621 and 125 sequences of COVID-19 and MERS downloaded and converted to polynomial datasets and seven attribute weighting (feature selection) approaches have been used for the analysis of genomic sequences of COVID-19 and MERS viruses. The end nucleotide sequences (from 29288 to the end genome positions) selected by the most attribute weighting models to be significantly different between two virus classes followed by smaller piece at 5700 and 1750 and 7600 nucleotide positions. These parts encode Nucleocapsid (N), Papin-like protease (NSP3) and NSP4 proteins of COVID-19. The finding for the first time reports the structural differences between two important viruses at the sequential level and paves the road to decipher new emerging COVID-19 virus high pathogenicity.

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Prediction of the SARS-CoV-2 (2019-nCoV) 3C-like protease (3CLpro) structure: virtual screening reveals velpatasvir, ledipasvir, and other drug repurposing candidates

Cited by 380 publications

References 34 publications

Identification of saquinavir as a potent inhibitor of dimeric SARS-CoV2 main protease through MM/GBSA

Identification of saquinavir as a potent inhibitor of dimeric SARS-CoV2 main protease through MM/GBSA

Global dynamics of SARS-CoV-2 clades and their relation to COVID-19 epidemiology

The first report of the most important sequential differences between COVID-19 and MERS viruses by attribute weighting models, the importance of Nucleocapsid (N) protein

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