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MeSH Disease

HGNC Genes

SARS-CoV-2 proteins

ComplexRdRp (4)

ProteinS (4)

NSP5 (3)

NSP3 (3)

NSP15 (2)


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SARS-CoV-2 Proteins
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    Different mutations in SARS-CoV-2 associate with severe and mild outcome

    Authors: Adam Nagy; Sandor Pongor; Balazs Gyorffy

    doi:10.1101/2020.10.16.20213710 Date: 2020-10-20 Source: medRxiv

    Introduction. Genomic alterations in a viral genome can lead to either better or worse outcome and identifying these mutations is of utmost importance. Here, we correlated protein-level mutations in the SARS-CoV-2 virus to clinical outcome. Methods. Mutations in viral sequences from the GISAID virus repository were evaluated by using hCoV-19/Wuhan/WIV04/2019 as the reference. Patient outcomes were classified as mild disease, hospitalization and severe disease ( death MESHD or documented treatment in an intensive-care unit). Chi-square test was applied to examine the association between each mutation and patient outcome. False discovery rate was computed to correct for multiple hypothesis testing and results passing a FDR cutoff of 5% were accepted as significant. Results. Mutations were mapped to amino acid changes for 2,120 non-silent mutations. Mutations correlated to mild outcome were located in the ORF8 PROTEIN, NSP6 PROTEIN, ORF3a PROTEIN, NSP4 PROTEIN NSP4 HGNC, and in the nucleocapsid phosphoprotein N. Mutations associated with inferior outcome were located in the surface ( S) glycoprotein PROTEIN, in the RNA dependent RNA polymerase PROTEIN, in the 3'-to5' exonuclease, in ORF3a PROTEIN, NSP2 HGNC NSP2 PROTEIN and N. Mutations leading to severe outcome with low prevalence were found in the surface ( S) glycoprotein PROTEIN and in NSP7 PROTEIN. Five out of 17 of the most significant mutations mapped onto a 10 amino acid long phosphorylated stretch of N indicating that in spite of obvious sampling restrictions the approach can find functionally relevant sites in the viral genome. Conclusions. We demonstrate that mutations in the viral genes may have a direct correlation to clinical outcome. Our results help to quickly identify SARS-CoV-2 infections MESHD harboring mutations related to severe outcome.

    Searching for target-specific and multi-targeting organics for Covid-19 MESHD in the Drugbank database with a double scoring approach

    Authors: Murugan Natarajan Arul; Sanjiv Kumar; Jeyaraman Jeyakanthan; Vaibhav Srivastav

    doi:10.21203/rs.3.rs-36233/v1 Date: 2020-06-16 Source: ResearchSquare

    The current outbreak of Covid-19 MESHD infection due to SARS-CoV-2, a virus from the coronavirus family, has become a major threat to human healthcare. The virus has already infected more than 5 M people and the number of deaths MESHD reported has reached more than 330 K which may be attributed to lack of medicine. The traditional drug discovery approach involves many years of rigorous research and development and demands for a huge investment which cannot be adopted for the ongoing pandemic infection MESHD. Rather we need a swift and cost-effective approach to inhibit and control the viral infection. With the help of computational screening approaches and by choosing appropriate chemical space, it is possible to identify lead drug-like compounds for Covid-19 MESHD. In this study, we have used the Drugbank database to screen compounds against the most important viral targets namely 3C-like protease ( 3CLpro PROTEIN), papain-like protease PROTEIN ( PLpro PROTEIN), RNA-dependent RNA polymerase PROTEIN ( RdRp PROTEIN) and the spike (S) protein PROTEIN. These targets play a major role in the replication/transcription and host cell recognition, therefore, are vital for the viral reproduction and spread of infection. As the structure based computational screening approaches are more reliable, we used the crystal structures for 3C-like main protease PROTEIN and spike protein PROTEIN. For the remaining targets, we used the structures based on homology modeling. Further, we employed two scoring methods based on binding free energies implemented in AutoDock Vina and molecular mechanics - Generalized Born surface area approach. Based on these results, we propose drug cocktails active against the three viral targets namely 3CL-pro, PLpro PROTEIN and RdRp PROTEIN. Interestingly, one of the identified compounds in this study i.e. Baloxavir marboxil has been under clinical trial for the treatment of Covid-19 MESHD infection. In addition, we identified a few compounds such as phthalocyanine, Tadalafil, Lonafarnib, Nilotinib, Dihydroergotamine, R-428 which can bind to all three targets simultaneously and can serve as multi-targeting drugs. Our study also included calculation of binding energies for various compounds currently under drug trials. Among these compounds, it is found that Remdesivir binds to targets, 3CLpro PROTEIN and RdRp PROTEIN with high binding affinity. Moreover, Baricitinib and Umifenovir were found to have superior target-specific binding while Darunavir is found to be a potential multi-targeting drug. As far as we know this is the first study where the compounds from the Drug-bank database are screened against four vital targets of SARS-CoV-2 and illustrates that the computational screening using a double scoring approach can yield potential drug-like compounds against Covid-19 MESHD infection.

    Shortlisting Phytochemicals Exhibiting Inhibitory Activity against Major Proteins of SARS-CoV-2 through Virtual Screening

    Authors: Saranya Nallusamy; Jayakanthan Mannu; Caroline Ravikumar; Kandavelmani Angamuthu; Bharathi Nathan; Kumaravadivel Nachimuthu; Gnanam Ramasamy; Raveendran Muthurajan; Mohankumar Subbarayalu; Kumar Neelakandan

    doi:10.21203/rs.3.rs-31834/v1 Date: 2020-05-27 Source: ResearchSquare

    Severe Acute Respiratory Syndrome Corona Virus 2 MESHD (SARS-CoV-2) declared as a pandemic by WHO that has affected more than 40 lakh peoples and caused death MESHD of more than 2 lakh individuals across the globe. Limited availability of genomic information of SARS-CoV-2 and non-availability of vaccines and effective drugs are major problems responsible for the ineffective control and management of this pandemic. Several attempts have been made to explore repurposing existing drugs known for their anti-viral activities, and test the traditional herbal medicines known for their health benefiting and immune boosting activity against SARS-CoV-2.In this study, efforts were made to examine the potential of 721 phytochemicals of 37 plant species in inhibiting major protein targets namely, spike glycoprotein PROTEIN, main protease PROTEIN (MPro), NSP3 HGNC NSP3 PROTEIN, NSP9 PROTEIN, NSP15 PROTEIN, NSP10 PROTEIN- NSP16 PROTEIN and RNA dependent RNA polymerase PROTEIN of SARS-CoV-2 through virtual screening approach. Results of our experiments revealed that SARS-CoV-2 MPro shared significant dissimilarities against SARS-CoVMPro and MERS-CoVMPro indicating the need for discovering novel drugs. This study has identified the phytochemical cyanin (Zingiber officinale) exhibiting broad spectrum inhibitory activity against main proteases PROTEIN of all the three Coronaviruses. Amentoflavone, agathisflavone, catechin-7-o-gallate and chlorogeninwere shown to exhibit multi target inhibitory activity. This study has identified Mangifera indica, Anacardium occidentale, Vitex negundo, Solanum nigrum, Pedalium murex, Terminalia chebula, Azadirachta indica, Cissus quadrangularis, Clerodendrum serratum and Ocimum basilicum as potential sources of phytochemicals combating n COVID-19 MESHD. More interestingly, this study has generated evidences for the anti-viral properties of the traditional herbal formulation “Kabasura kudineer” recommended by AYUSH, a unit of Government of India. Testing of short listed phytochemicals through clinical trials will help in developing effective formulation for management of this pandemic disease. Genomic analysis of identified herbal plants will help in unravelling molecular complexity of therapeutic and anti-viral properties and will pave way for designing synthetic drugs. 

    Not One, But Five: Virtual Screening-Driven Drug Discovery of SARS-CoV2 Enzyme Inhibitors Targeting Viral Attachment, Replication and Post-Translational Infection Mechanisms

    Authors: Mark Tristan J. Quimque; Kin Israel Notarte; Rey Arturo T. Fernandez; Mark Andrew O. Mendoza; Rhenz Alfred D. Liman; Justin Allen K. Lim; Luis Agustin E. Pilapil; Jehiel Karsten H. Ong; Adriel M. Pastrana; Allan Patrick Macabeo

    doi:10.26434/chemrxiv.12170424.v2 Date: 2020-04-28 Source: ChemRxiv

    The novel coronavirus SARS-CoV2, the causative agent of the worldwide pandemic disease COVID-19 MESHD, emerged in December 2019 forcing lockdown of communities in many countries. The absence of specific drugs and vaccines, the rapid transmission of the virus, and the increasing number of deaths MESHD worldwide have necessitated the need to discover substances that can be tapped for drug development. With the aid of bioinformatics and computational modelling, ninety seven secondary metabolites from fungi previously reported to exhibit antiviral properties were docked onto SARS-CoV2 enzymes involved in viral attachment, replication and post-translational mechanisms followed by in silico ADMET prediction (absorption, distribution, metabolism, excretion and toxicity MESHD) of the hit compounds. Thus, two fumiquinazoline alkaloids quinadoline B (19), scedapin C (15), and the polyketide isochaetochromin D1 (8) exhibited high binding affinities depending on the target protein. The compounds were active against the cysteine proteases, papain-like PROTEIN protease ( PLpro PROTEIN) and chymotrypsin-like protease ( 3CLpro PROTEIN) which are involved in post-translational modifications, RNA-directed RNA polymerase ( RdRp PROTEIN) which is essential in viral replication, non-structural protein 15 PROTEIN (nsp15) which is involved in evasion of host immunity, and the spike protein PROTEIN which is responsible for binding to GRP78 HGNC. Quinadoline B (19) was predicted to confer favorable ADMET values, high gastrointestinal absorptive probability and poor blood-brain barrier crossing capacities.

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MeSH Disease
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