QMEANDisCo—distance constraints applied on model quality estimation

Studer, Gabriel; Rempfer, Christine; Waterhouse, Andrew; Gumienny, Rafal; Haas, Juergen; Schwede, Torsten

doi:10.1093/bioinformatics/btaa058

Cited by 161 publications

(166 citation statements)

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“…The model quality (global and per-residue) of TMPRSS2 obtained was evaluated with the QMEAN scoring function (Studer et al., 2020 ). A near-zero QMEAN score is a good value in terms of the quality of the fit between model structure and the experimental structure.…”

Section: Methodsmentioning

confidence: 99%

In silico analysis of the interactions of certain flavonoids with the receptor-binding domain of 2019 novel coronavirus and cellular proteases and their pharmacokinetic properties

İstifli

Netz

Tepe

et al. 2020

Journal of Biomolecular Structure and Dynamics

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Coronavirus Disease 2019 (COVID-19) has infected more than thirty five million people worldwide and caused nearly 1 million deaths as of October 2020. The microorganism causing COVID-19 was named as Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2 or 2019-nCoV). The aim of this study was to investigate the interactions of twenty-three phytochemicals belonging to different flavonoid subgroups with the receptor binding domain (RBD) of the spike glycoprotein of 2019-nCoV, and cellular proteases [transmembrane serine protease 2 (TMPRSS2), cathepsin B and L (CatB/L)]. The compounds interacted more strongly with CatB and CatL than with the other proteins. Van der Waals and hydrogen bonds played an important role in the receptor-ligand interactions. As a result of RBCI (relative binding capacity index) analysis conducted to rank flavonoids in terms of their interactions with the target proteins, (-) -epicatechin gallate interacted strongly with all the proteins studied. The results obtained from molecular dynamics and molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) methods also supported this data. According to Lipinski's rule of five, (-) -epicatechin gallate showed drug-likeness properties. Although this molecule is not capable of crossing the blood-brain barrier (BBB), it was concluded that (-) -epicatechin gallate can be evaluated as a candidate molecule in drug development studies against 2019-nCoV since it was not the substrate of P-gp (P-glycoprotein), did not inhibit any of the cytochrome Ps, and did not show AMES toxicity or hepatotoxicity on eukaryotic cells.

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Section: Methodsmentioning

confidence: 99%

In silico analysis of the interactions of certain flavonoids with the receptor-binding domain of 2019 novel coronavirus and cellular proteases and their pharmacokinetic properties

İstifli

Netz

Tepe

et al. 2020

Journal of Biomolecular Structure and Dynamics

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“…The quality was assessed by the QMEAN scoring function. QMEANS value [ 19 , 20 ] and Generalized Quantum Master Equations (GMQE) value of the model was found to be −1.43 and 0.53, respectively. We further analyzed the homology model of TMPRSS2 (344 amino acid residues) with the help of RAMPAGE software and noticed that 92.7% of the total residues were in favored regions, 6.7% of the total residues were in allowed regions and only 0.6% of the total residues were in outlier region ( Supplementary Material Figure S1 ).…”

Section: Resultsmentioning

confidence: 99%

Protease Inhibitory Effect of Natural Polyphenolic Compounds on SARS-CoV-2: An In Silico Study

et al. 2020

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The current pandemic, caused by SARS-CoV-2 virus, is a severe challenge for human health and the world economy. There is an urgent need for development of drugs that can manage this pandemic, as it has already infected 19 million people and led to the death of around 711,277 people worldwide. At this time, in-silico studies are providing lots of preliminary data about potential drugs, which can be a great help in further in-vitro and in-vivo studies. Here, we have selected three polyphenolic compounds, mangiferin, glucogallin, and phlorizin. These compounds are isolated from different natural sources but share structural similarities and have been reported for their antiviral activity. The objective of this study is to analyze and predict the anti-protease activity of these compounds on SARS-CoV-2main protease (Mpro) and TMPRSS2 protein. Both the viral protein and the host protein play an important role in the viral life cycle, such as post-translational modification and viral spike protein priming. This study has been performed by molecular docking of the compounds using PyRx with AutoDock Vina on the two aforementioned targets chosen for this study, i.e., SARS-CoV-2 Mpro and TMPRSS2. The compounds showed good binding affinity and are further analyzed by (Molecular dynamic) MD and Molecular Mechanics Poisson-Boltzmann Surface Area MM-PBSA study. The MD-simulation study has predicted that these natural compounds will have a great impact on the stabilization of the binding cavity of the Mpro of SARS-CoV-2. The predicted pharmacokinetic parameters also show that these compounds are expected to have good solubility and absorption properties. Further predictions for these compounds also showed no involvement in drug-drug interaction and no toxicity.

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“…SWISS-MODEL was utilized to generate a SARS-CoV-2 spike protein structure prior to the availability of Cryo-EM or X-ray crystallography data in February of 2020. 64,65,66,67,68,69 The SARS-CoV-2 spike protein structure was aligned with SARS-CoV-1 spike protein bound to ACE2 (PDB ID 6CS2) using PyMOL (The PyMOL Molecular Graphics System, Version 2.3.5 Schrödinger, LLC.). This structure was then run through PDBePISA to determine the Gibbs free energy (∆G) and predicted amino acid interactions between the SARS-CoV-2 spike protein and the ACE2 receptor.…”

Section: Simulation and Docking Of Sars-cov-2 Spike Protein In The Abmentioning

confidence: 99%

Peptide Antidotes to SARS-CoV-2 (COVID-19)

Watson

Ferreira

Hwang

et al. 2020

Preprint

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The design of an immunogenic scaffold that serves a role in treating a pathogen, and can be rapidly and predictively modeled, has remained an elusive feat. Here, we demonstrate that SARS-BLOCK™ synthetic peptide scaffolds act as antidotes to SARS-CoV-2 spike protein-mediated infection of human ACE2-expressing cells. Critically, SARS-BLOCK™ peptides are able to potently and competitively inhibit SARS-CoV-2 S1 spike protein receptor binding domain (RBD) binding to ACE2, the main cellular entry pathway for SARS-CoV-2, while also binding to neutralizing antibodies against SARS-CoV-2. In order to create this potential therapeutic antidote-vaccine, we designed, simulated, synthesized, modeled epitopes, predicted peptide folding, and characterized behavior of a novel set of synthetic peptides. The biomimetic technology is modeled off the receptor binding motif of the SARS-CoV-2 coronavirus, and modified to provide enhanced stability and folding versus the truncated wildtype sequence. These novel peptides attain single-micromolar binding affinities for ACE2 and a neutralizing antibody against the SARS-CoV-2 receptor binding domain (RBD), and demonstrate significant reduction of infection in nanomolar doses. We also demonstrate that soluble ACE2 abrogates binding of RBD to neutralizing antibodies, which we posit is an essential immune-evasive mechanism of the virus. SARS-BLOCK™ is designed to “uncloak” the viral ACE2 coating mechanism, while also binding to neutralizing antibodies with the intention of stimulating a specific neutralizing antibody response. Our peptide scaffolds demonstrate promise for future studies evaluating specificity and sensitivity of immune responses to our antidote-vaccine. In summary, SARS-BLOCK™ peptides are a promising COVID-19 antidote designed to combine the benefits of a therapeutic and vaccine, effectively creating a new generation of prophylactic and reactive antiviral therapeutics whereby immune responses can be enhanced rather than blunted.

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QMEANDisCo—distance constraints applied on model quality estimation

Cited by 161 publications

References 0 publications

In silico analysis of the interactions of certain flavonoids with the receptor-binding domain of 2019 novel coronavirus and cellular proteases and their pharmacokinetic properties

In silico analysis of the interactions of certain flavonoids with the receptor-binding domain of 2019 novel coronavirus and cellular proteases and their pharmacokinetic properties

Protease Inhibitory Effect of Natural Polyphenolic Compounds on SARS-CoV-2: An In Silico Study

Peptide Antidotes to SARS-CoV-2 (COVID-19)

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