Corpus overview


Overview

MeSH Disease

HGNC Genes

SARS-CoV-2 proteins

NSP5 (412)

ProteinS (63)

NSP3 (57)

ComplexRdRp (51)

ProteinN (11)


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SARS-CoV-2 Proteins
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    Structure-based virtual screening suggests inhibitors of 3-Chymotrypsin-Like Protease of SARS-CoV-2 from Vernonia amygdalina and Occinum gratissimum

    Authors: Gideon A. Gyebi; Abdo A. Elfiky; Oludare M. Ogunyemi; Ibrahim M. Ibrahim; Adegbenro P. Adegunloye; Joseph O. Adebayo; Charles O. Olaiya; Joshua Ocheje; Mercy M Fabusiwa

    doi:10.21203/rs.3.rs-301445/v1 Date: 2021-03-05 Source: ResearchSquare

    An in-house library of 173 phytocompound structures from Vernonia amygdalina and Occinum gratissimum was screened against the active region of 3-Chymotrypsin-Like Protease ( 3CLpro PROTEIN) of SARS-CoV-2 in silico. Based on docking scores and reference inhibitors, a hit- list of 21 phytocompounds, with binding energies ranging from − 7.2 to -8.0 kcal/mol, was initially generated. Further docking against the 3CLpro PROTEIN of related coronaviruses ( SARS-CoV MESHD and MERS-CoV), docking to 5 different representative conformations generated from the cluster analysis of SARS-CoV-2 3CLpro PROTEIN molecular dynamics simulation ( MDS MESHD) trajectories, and in silico drug-likeness analyses, revealed two drug-like terpenoid structures as promising non-covalent inhibitors of SARS-CoV-2 3CLPro viz: neoandrographolide and vernolide. These terpenoid structures are accommodated within the substrate-binding pocket, and interacted with the catalytic dyad, the oxyanion loop (residues 138–145), and the S1/S2 subsites of the enzyme active site. With the aid of an array of hydrogen bonds and hydrophobic interactions with residues 142–145, these phytocompounds may stabilize the conformation of the flexible oxyanion loop; and thereby interfere with the tetrahedral oxyanion intermediate formation during proteolytic cleavage. Molecular dynamics simulation and binding free energy calculation further revealed that the terpenoid-enzyme complexes exhibit strong interactions and structural stability, which could be adapted for experimental models.

    A novel conformational state for SARS-CoV-2 main protease PROTEIN

    Authors: Emanuele Fornasier; Maria Ludovica Macchia; Gabriele Giachin; Alice Sosic; Matteo Pavan; Mattia Sturlese; Cristiano Salata; Stefano Moro; Barbara Gatto; Massimo Bellanda; Roberto Battistutta

    doi:10.1101/2021.03.04.433882 Date: 2021-03-04 Source: bioRxiv

    The SARS-CoV-2 main protease PROTEIN ( Mpro PROTEIN) has a pivotal role in mediating viral genome replication and transcription of coronavirus, making it a promising target for drugs against Covid-19 pandemic MESHD. Here we present a crystal structure of Mpro PROTEIN disclosing new structural features of key regions of the enzyme. We show that the oxyanion loop, involved in substrate recognition and enzymatic activity, can adopt a new conformation, which is stable and significantly different from the known ones. In this new state the S1 subsite of the substrate binding region is completely reshaped and a new cavity near the S2 subsite is created. This new structural information expands the knowledge of the conformational space available to Mpro PROTEIN, paving the way for the design of novel classes of inhibitors specifically designed to target this unprecedented binding site conformation, thus enlarging the chemical space for urgent antiviral drugs against Covid-19 pandemic MESHD.

    A pharmacophore model for SARS-CoV-2 3CLpro PROTEIN small molecule inhibitors and in vitro experimental validation of computationally screened inhibitors

    Authors: Enrico Glaab; Ganesh Babu Manoharan; Daniel Abankwa

    doi:10.1101/2021.03.02.433618 Date: 2021-03-03 Source: bioRxiv

    Among the biomedical efforts in response to the current coronavirus ( COVID-19 MESHD) pandemic, pharmacological strategies to reduce viral load in patients with severe forms of the disease are being studied intensively. One of the main drug target proteins proposed so far is the SARS-CoV-2 viral protease 3CLpro PROTEIN (also called Mpro PROTEIN), an essential component for viral replication. Ongoing ligand- and receptor-based computational screening efforts would be facilitated by an improved understanding of the electrostatic, hydrophobic and steric features that characterize small molecule inhibitors binding stably to 3CLpro PROTEIN, as well as by an extended collection of known binders. Here, we present combined virtual screening, molecular dynamics simulation, machine learning and in vitro experimental validation analyses which have led to the identification of small molecule inhibitors of 3CLpro PROTEIN with micromolar activity, and to a pharmacophore model that describes functional chemical groups associated with the molecular recognition of ligands by the 3CLpro PROTEIN binding pocket. Experimentally validated inhibitors using a ligand activity assay include natural compounds with available prior knowledge on safety and bioavailability properties, such as the natural compound rottlerin (IC50 = 37 mcM), and synthetic compounds previously not characterized (e.g. compound CID 46897844, IC50 = 31 mcM). In combination with the developed pharmacophore model, these and other confirmed 3CLpro PROTEIN inhibitors may provide a basis for further similarity-based screening in independent compound databases and structural design optimization efforts, to identify 3CLpro PROTEIN ligands with improved potency and selectivity. Overall, this study suggests that the integration of virtual screening, molecular dynamics simulations and machine learning can facilitate 3CLpro PROTEIN-targeted small molecule screening investigations. Different receptor-, ligand- and machine learning-based screening strategies provided complementary information, helping to increase the number and diversity of identified active compounds. Finally, the resulting pharmacophore model and experimentally validated small molecule inhibitors for 3CLpro PROTEIN provide resources to support follow-up computational screening efforts for this drug target.

    Atorvastatin effectively inhibits late replicative cycle steps of SARS-CoV-2 in vitro

    Authors: Maria Isabel Zapata-Cardona; Lizdany Flórez-Álvarez; Wildeman Zapata-Builes; Ariadna Guerra-Sandoval; Carlos Guerra-Almonacid; Jaime Hincapié-García; Maria Teresa Rugeles; Juan Carlos Hernández

    doi:10.1101/2021.03.01.433498 Date: 2021-03-03 Source: bioRxiv

    Introduction: SARS-CoV-2 has caused a pandemic of historic proportions and continues to spread worldwide. Currently, there is no effective therapy against this virus. This article evaluated the in vitro antiviral effect of Atorvastatin against SARS-CoV-2 and also identified the interaction affinity between Atorvastatin and three SARS-CoV-2 proteins MESHD, using in silico structure-based molecular docking approach. Materials and methods: The antiviral activity of Atorvastatin against SARS-CoV-2 was evaluated by three different treatment strategies using a clinical isolate of SARS-CoV-2. The interaction of Atorvastatin with Spike, RNA-dependent RNA polymerase PROTEIN ( RdRp PROTEIN) and 3C-like protease ( 3CLpro PROTEIN) was evaluated by molecular docking. Results: Atorvastatin showed anti-SARS-CoV-2 activity of 79%, 54.8%, 22.6% and 25% at 31.2, 15.6, 7.9, and 3.9 {micro}M, respectively, by pre-post-treatment strategy. In addition, atorvastatin demonstrated an antiviral effect of 26.9% at 31.2 {micro}M by pre-infection treatment. This compound also inhibited SARS-CoV-2 in 66.9%, 75%, 27.9% and 29.2% at concentrations of 31.2, 15.6, 7.9, and 3.9 {micro}M, respectively, by post-infection treatment. The interaction of atorvastatin with SARS-CoV-2 Spike PROTEIN SARS-CoV-2 Spike MESHD, RdRp PROTEIN and 3CL protease PROTEIN yielded a binding affinity of -8.5 Kcal/mol, -6.2 Kcal/mol, and -7.5 Kcal/mol, respectively. Conclusion: Our study demonstrated the in vitro anti-SARS-CoV-2 activity of Atorvastatin, mainly against the late steps of the viral replicative cycle. A favorable binding affinity with viral proteins by bioinformatics methods was also shown. Due to its low cost, availability, well-established safety and tolerability, and the extensive clinical experience of atorvastatin, it could prove valuable in reducing morbidity and mortality from COVID-19 MESHD.

    High-content screening of coronavirus genes for innate immune suppression revealsenhanced potency of SARS-CoV-2 proteins

    Authors: Erika J Olson; David M Brown; Timothy Z Chang; Lin Ding; Tai L Ng; H. Sloane Weiss; Peter Koch; Yukiye Koide; Nathan Rollins; Pia Mach; Tobias Meisinger; Trenton Bricken; Joshus Rollins; Yun Zhang; Colin Molloy; Yun Zhang; Briodget N Queenan; Timothy Mitchison; Debora Marks; Jeffrey C Way; John I Glass; Pamela A Silver

    doi:10.1101/2021.03.02.433434 Date: 2021-03-02 Source: bioRxiv

    Suppression of the host intracellular innate immune system is an essential aspect of viral replication. Here, we developed a suite of medium-throughput high-content cell-based assays to reveal the effect of individual coronavirus proteins on antiviral innate immune pathways. Using these assays, we screened the 196 protein products of seven coronaviruses (SARS-CoV-2,SARS-CoV-1, 229E, NL63, OC43, HKU1 and MERS). This includes a previously unidentified gene in SARS-CoV-2 encoded within the Spike gene. We observe immune-suppressing activity in both known host-suppressing genes (e PROTEIN.g., NSP1, Orf6, NSP3 PROTEIN, and NSP5 PROTEIN) as well as other coronavirus genes, including the newly identified SARS-CoV-2 protein. Moreover, the genes encoded by SARS-CoV-2 are generally more potent immune suppressors than their homologues from the other coronaviruses. This suite of pathway-based and mechanism-agnostic assays could serve as the basis for rapid in vitro prediction of the pathogenicity of novel viruses based on provision of sequence information alone.

    Nature Potential for COVID-19 MESHD: Targeting SARS-CoV-2 Mpro PROTEIN Inhibitor with Bioactive Compound

    Authors: Kaushik Kumar Bharadwaj; Tanmay Sarkar; Arabinda Ghosh; Debabrat Baishya; Bijuli Rabha; Manasa Kumar Panda; Bryan R. Nelson; Akbar John; Hassan I. Sheikh; Bisnu Prasad Dash; Hisham A. Edinur; Siddhartha Pati

    doi:10.26434/chemrxiv.14112515.v2 Date: 2021-03-01 Source: ChemRxiv

    Corona viruses were first identified in 1931 and SARS-CoV-2 is the most recent. COVID-19 MESHD is a pandemic that put most of the world on lockdown and the search for therapeutic drugs is still on-going. Therefore, this study uses in silico screening to identify natural bioactive compounds from fruits, herbaceous plants and marine invertebrates that are able to inhibit protease activity in SARS-CoV-2(PDB: 6LU7). We have used various screening strategies such as drug likeliness, antiviral activity value prediction, molecular docking, ADME (absorption, distribution, metabolism, and excretion), molecular dynamics ( MD MESHD) simulation and MM/GBSA (molecular mechanics/generalized born and surface area continuum solvation). 17 compounds were shortlisted using Lipinski’s rule. 5 compounds revealed significantly good predicted antiviral activity values and out of them only 2 compounds, Macrolactin A and Stachyflin, showed good binding energy values of -9.22 and -8.00 kcal/mol within the binding pocket, catalytic residues ( HIS MESHD 41 and CYS 145) of Mpro PROTEIN. These two compounds were further analyzed for their ADME properties. The ADME evaluation of these 2 compounds suggested that they could be effective as therapeutic agents for developing drugs for clinical trials. MD simulations showed that protein-ligand complexes of Macrolactin A and Stachyflin were stable for 100 nano seconds. The MM/GBSA calculations of Mpro PROTEIN – Macrolactin A complex indicated higher binding free energy (-42.58 ± 6.35 kcal/mol) with Mpro PROTEIN protein target receptor (6LU7). DCCM and PCA analysis on the residual movement in the MD trajectories confirmed the good stability on Macrolactin A bound state of 6LU7. This signify the stable conformation of 6LU7 with high binding energy with Macrolactin A. Thus, this study showed that Macrolactin A could be an effective therapeutical agent for SARS-CoV-2protease MESHD (6LU7) inhibition. Additional in vitro and in vivo validations are needed to determine efficacy and dose of Macrolactin A in biological systems.

    The impact of mutations on the structural and functional properties of SARS-CoV-2 proteins: A comprehensive bioinformatics analysis

    Authors: Aqsa Ikram; Anam Naz; Faryal Awan; Bisma Rauff; Ayesha Obaid; Mohamad S. Hakim; Arif Malik

    doi:10.1101/2021.03.01.433340 Date: 2021-03-01 Source: bioRxiv

    An in-depth analysis of first wave SARS-CoV-2 genome is required to identify various mutations that significantly affect viral fitness MESHD. In the present study, we have performed comprehensive in-silico mutational analysis of 3C-like protease ( 3CLpro PROTEIN), RNA dependent RNA polymerase PROTEIN ( RdRp PROTEIN), and spike (S) proteins PROTEIN with the aim of gaining important insights into first wave virus mutations and their functional and structural impact on SARS-CoV-2 proteins. Our integrated analysis gathered 3465 SARS-CoV-2 sequences and identified 92 mutations in S, 37 in RdRp PROTEIN, and 11 in 3CLpro PROTEIN regions. The impact of those mutations was also investigated using various in silico approaches. Among these 32 mutations in S, 15 in RdRp PROTEIN, and 3 in 3CLpro PROTEIN proteins are found to be deleterious in nature and could alter the structural and functional behavior of the encoded proteins. D614G mutation in spike and P323L in RdRp PROTEIN are the globally dominant variants with a high frequency. Most of them have also been found in the binding moiety of the viral proteins which determine their critical involvement in the host-pathogen interactions and drug targets. The findings of the current study may facilitate better understanding of COVID-19 MESHD diagnostics, vaccines, and therapeutics.

    Synthesis of Novel Halogenated Heterocyclic compounds and their uses as Target SARS-CoV-2 main Protease PROTEIN ( Mpro PROTEIN) and Potential Anti- Covid-19 MESHD

    Authors: Rafat Mohareb; Fahad M. Almutairi; Abdo A. Elfiky; Mahmoud A.A. Mahmoud; Wagnat W. Wardakhan; Mervat S. Mohamed; Ali Saber Abdelhameed

    doi:10.21203/rs.3.rs-284501/v1 Date: 2021-02-27 Source: ResearchSquare

    Since the first appearance of the coronavirus disease-2019 ( COVID-19 MESHD) in Wuhan, China, in December 2019, it has been spreading globally with devastating ramifications. The lack of anti- COVID-19 MESHD treatment to date warrants urgent research into potential therapeutic targets. Virtual drug screening techniques enable the identification of novel compounds that are capable of targeting the severe acute respiratory syndrome coronavirus 2 MESHD (SARS-CoV-2) main protease PROTEIN ( Mpro PROTEIN). The latter plays a fundamental role in mediating viral replication and transcription, rendering it an attractive drug target. In this study, twenty six novel halogenated, heterocyclic compounds, which can inhibit Mpro PROTEIN, were tested by molecular docking combined with molecular dynamics simulation. Three compounds showed the highest binding affinity to the protein active site and their binding modes coincide with that of Nelfinavir. The binding of the halogenated compounds to Mpro PROTEIN may inhibit the replication and transcription of SARS-CoV-2 and, ultimately, stop the virallife cycle. In times of dire need for anti- COVID-19 MESHD treatment, this study lays the groundwork for further experimental research to investigate the efficacy and potential medical uses of these compounds to treat COVID-19 MESHD. Novel compounds including fused thiophene, pyrimidine and pyran derivatives were tested against human RNA N7-MTase ( hRNMT HGNC) and selected viral N7-MTases such as SARS-CoV MESHD nsp14 and Vaccinia D1-D12 complex to evaluate their specificity and their molecular modeling was also studied in the aim of producing anti covid-19 MESHD target molecules.

    The proximal proteome of 17 SARS-CoV-2 proteins links to disrupted antiviral signaling and host translation

    Authors:

    doi:10.1101/2021.02.23.432450 Date: 2021-02-23 Source: bioRxiv

    Viral proteins localize within subcellular compartments to subvert host machinery and promote pathogenesis. To study SARS-CoV-2 biology, we generated an atlas of 2422 human proteins vicinal to 17 SARS-CoV-2 viral proteins using proximity proteomics. This identified viral proteins at specific intracellular locations, such as association of accessary proteins with intracellular membranes, and projected SARS-CoV-2 impacts on innate immune signaling, ER-Golgi transport, and protein translation. It identified viral protein adjacency to specific host proteins whose regulatory variants are linked to COVID-19 MESHD severity, including the TRIM4 HGNC interferon signaling regulator which was found proximal to the SARS-CoV-2 M protein PROTEIN. Viral NSP1 HGNC protein adjacency to the EIF3 HGNC complex was associated with inhibited host protein translation whereas ORF6 PROTEIN localization with MAVS HGNC was associated with inhibited RIG-I HGNC 2CARD-mediated IFNB1 HGNC promoter activation. Quantitative proteomics identified candidate host targets for the NSP5 HGNC NSP5 PROTEIN protease, with specific functional cleavage sequences in host proteins CWC22 HGNC and FANCD2 HGNC. This data resource identifies host factors proximal to viral proteins in living human cells and nominates pathogenic mechanisms employed by SARS-CoV-2. Author SummarySARS-CoV-2 is the latest pathogenic coronavirus to emerge as a public health threat. We create a database of proximal host proteins to 17 SARS-CoV-2 viral proteins. We validate that NSP1 HGNC is proximal to the EIF3 HGNC translation initiation complex and is a potent inhibitor of translation. We also identify ORF6 PROTEIN antagonism of RNA-mediate innate immune signaling. We produce a database of potential host targets of the viral protease NSP5 HGNC NSP5 PROTEIN, and create a fluorescence-based assay to screen cleavage of peptide sequences. We believe that this data will be useful for identifying roles for many of the uncharacterized SARS-CoV-2 proteins and provide insights into the pathogenicity of new or emerging coronaviruses.

    Active constituents and Molecular Analysis of Psidium guajava Against Multiple Protein of SARS-CoV-2

    Authors: Fadilah Fadilah; Linda Erlina; Rafika Indah Paramita; Khaerunissa Anbar Istiadi; Raden Rara Diah Handayani

    doi:10.21203/rs.3.rs-271919/v1 Date: 2021-02-23 Source: ResearchSquare

    Background The severe acute respiratory syndrome MESHD COVID-19 MESHD declared as a global pandemic by the World Health Organization has become the present wellbeing worry to the whole world. The latest development of COVID-19 MESHD spread in Indonesia has reached 1.024.298 cases, with 28.855 patients died, updated on January 28, 2021. Unfortunately, these numbers continue to overgrow, and no drug has yet been approved for effective treatment. There is an emergent need to search for possible medications and explore the potential of Indonesian herbal compounds. Ministry of Health Indonesia stated that Psidium guajava can be use as daily nutritional supplement during COVID-19 pandemic MESHD. This study aims to determine the potential active constituents in Psidium guajava as an inhibitor for multiple SARS-CoV-2 proteins using molecular analysis.Methods Molecular docking was performed by using Autodocktools 1.5.6. We performed a structure-based virtual screening of fourteen 3D structure of Psidium guajava compounds, three antivirals (lopinavir, remdesivir, and ritonavir) against multiple SARS-CoV-2 proteins. We download the main protease PROTEIN (3CLPro), Papain Like Protease PROTEIN (PL Pro), MPro, Spike and ACE2 HGNC as protein target from human against from Protein Data Bank (PDB). We used PyMOL to analyse the interactions between the SARS-CoV-2 proteins and 14 compounds from Psidium guajava and three antiviral (lopinavir, remdesivir and ritonavir) used as positive control.Results Based on the molecular docking analysis, it was found there are two potential compounds that showed higher binding affinity score namely gamma sitosterol and peri-xanthenoxanthene-4,10-dione,2,8-bis (1-methylethyl).Conclusions Gamma sitosterol and peri-xanthenoxanthene-4,10-dione,2,8-bis (1-methylethyl) from Psidium guajava have potential as antiviral candidates for SARS-CoV-2 multiple proteins such as main protease PROTEIN (3CLPro), Papain Like Protease PROTEIN (PL Pro), MPro, Spike and ACE2 HGNC.

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins


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