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, K.P.

doi:10.12688/f1000research.22457.1

Cited by 224 publications

(260 citation statements)

References 31 publications

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“…The lack of success might be related to the above-mentioned plasticity of the binding cavity. Some of these compounds have been used for docking and virtual screening research aimed not only at SARS-CoV [44,45] but also at the novel SARS-CoV-2 [15][16][17][18][19][20][21]. Such an approach focuses mostly on the structural similarity between the binding pockets, but ignores the fact that the actual available binding space differs significantly.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, an in silico attempt has already been made involving a massive virtual screening for Mpro inhibitors of SARS-CoV-2 using Deep Docking [15]. Other recent attempts focused on virtual screening for putative inhibitors of the same main protease of SARS-CoV-2 on the basis of the clinically approved drugs [16][17][18][19][20][21], and also on the basis of the compounds from different databases or libraries [22][23][24]. However, none of such attempts is likely to lead to clinical advances in the fight against SARS-CoV-2 for reasons we elaborate below.…”

Section: Introductionmentioning

confidence: 99%

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Structural and Evolutionary Analysis Indicate That the SARS-CoV-2 Mpro Is a Challenging Target for Small-Molecule Inhibitor Design

Bzówka

Mitusińska

Raczyńska

et al. 2020

IJMS

156

194

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The novel coronavirus whose outbreak took place in December 2019 continues to spread at a rapid rate worldwide. In the absence of an effective vaccine, inhibitor repurposing or de novo drug design may offer a longer-term strategy to combat this and future infections due to similar viruses. Here, we report on detailed classical and mixed-solvent molecular dynamics simulations of the main protease (Mpro) enriched by evolutionary and stability analysis of the protein. The results were compared with those for a highly similar severe acute respiratory syndrome (SARS) Mpro protein. In spite of a high level of sequence similarity, the active sites in both proteins showed major differences in both shape and size, indicating that repurposing SARS drugs for COVID-19 may be futile. Furthermore, analysis of the binding site's conformational changes during the simulation time indicated its flexibility and plasticity, which dashes hopes for rapid and reliable drug design. Conversely, structural stability of the protein with respect to flexible loop mutations indicated that the virus' mutability will pose a further challenge to the rational design of small-molecule inhibitors. However, few residues contribute significantly to the protein stability and thus can be considered as key anchoring residues for Mpro inhibitor design.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Structural and Evolutionary Analysis Indicate That the SARS-CoV-2 Mpro Is a Challenging Target for Small-Molecule Inhibitor Design

Bzówka

Mitusińska

Raczyńska

et al. 2020

IJMS

156

194

View full text Add to dashboard Cite

show abstract

“…The SARS-CoV-2 pandemic (Poon and Peiris, 2020) poses the greatest global health and socioeconomic threat since the second world war. Complete genomic sequences of viral isolates from diverse geographic sites, have rapidly been made available through dedicated resources (Shu andMcCauley, 2017, Goodacre et al,2018) facilitating comparative genomics studies, identification of putative therapeutic targets (Zhou et al, 2020, Chen et al 2020, Robson 2020) and the development of effective prevention and monitoring strategies (Qiang et al 2020). Analyses of available genomic sequences, according to GISAID EpiCoV, suggest major viral clades, S, V and G which, collectively, circumscribe more than 69% of the characterised isolates.…”

Section: Introductionmentioning

confidence: 99%

Comparative genomics suggests limited variability and similar evolutionary patterns between major clades of SARS-CoV-2

Chiara

Horner

Gissi

et al. 2020

Preprint

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Phylogenomic analysis of SARS-CoV-2 as available from publicly available repositories suggests the presence of 3 prevalent groups of viral episomes (super-clades), which are mostly associated with outbreaks in distinct geographic locations (China, USA and Europe). While levels of genomic variability between SARS-CoV-2 isolates are limited, to our knowledge, it is not clear whether the observed patterns of variability in viral super-clades reflect ongoing adaptation of SARS-CoV-2, or merely genetic drift and founder effects. Here, we analyze more than 1100 complete, high quality SARS-CoV-2 genome sequences, and provide evidence for the absence of distinct evolutionary patterns/signatures in the genomes of the currently known major clades of SARS-CoV-2. Our analyses suggest that the presence of distinct viral episomes at different geographic locations are consistent with founder effects, coupled with the rapid spread of this novel virus. We observe that while cross species adaptation of the virus is associated with hypervariability of specific protein coding regions (including the RDB domain of the spike protein), the more variable genomic regions between extant SARS-CoV-2 episomes correspond with the 3' and 5' UTRs, suggesting that at present viral protein coding genes should not be subjected to different adaptive evolutionary pressures in different viral strains. Although this study can not be conclusive, we believe that the evidence presented here is strongly consistent with the notion that the biased geographic distribution of SARS-CoV-2 isolates should not be associated with adaptive evolution of this novel pathogen.

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“…Sang et al verified the assumption of using HIV-1 protease inhibitors as anti-SARS drugs by targeting SARS-Co-V 3CLpro [73]. The authors employed six approved anti-HIV-1 drugs to investigate their binding interactions between 3CLpro.…”

Section: Mechanism Of Actionmentioning

confidence: 99%

On Facing the SARS-CoV-2 (COVID-19) with Combination of Nanomaterials and Medicine: Possible Strategies and First Challenges

et al. 2020

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Global health is facing the most dangerous situation regarding the novel severe acute respiratory syndrome called coronavirus 2 (SARS-CoV-2), which is widely known as the abbreviated COVID-19 pandemic. This is due to the highly infectious nature of the disease and its possibility to cause pneumonia induced death in approximately 6.89% of infected individuals (data until 27 April 2020). The pathogen causing COVID-19 is called severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which is believed to be originated from the Wuhan Province in China. Unfortunately, an effective and approved vaccine for SARS-CoV-2 virus is still not available, making the situation more dangerous and currently available medical care futile. This unmet medical need thus requires significant and very urgent research attention to develop an effective vaccine to address the SARS-CoV-2 virus. In this review, the state-of-the-art drug design strategies against the virus are critically summarized including exploitations of novel drugs and potentials of repurposed drugs. The applications of nanochemistry and general nanotechnology was also discussed to give the status of nanodiagnostic systems for COVID-19.

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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 224 publications

References 31 publications

Structural and Evolutionary Analysis Indicate That the SARS-CoV-2 Mpro Is a Challenging Target for Small-Molecule Inhibitor Design

Structural and Evolutionary Analysis Indicate That the SARS-CoV-2 Mpro Is a Challenging Target for Small-Molecule Inhibitor Design

Comparative genomics suggests limited variability and similar evolutionary patterns between major clades of SARS-CoV-2

On Facing the SARS-CoV-2 (COVID-19) with Combination of Nanomaterials and Medicine: Possible Strategies and First Challenges

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