Corpus overview


MeSH Disease

HGNC Genes

SARS-CoV-2 proteins

NSP5 (390)

ProteinS (61)

NSP3 (54)

ComplexRdRp (49)

ProteinN (11)


SARS-CoV-2 Proteins
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    Efficiency Improvements and Discovery of New Substrates for a SARS-CoV-2 Main Protease PROTEIN FRET Assay


    doi:10.1101/2021.02.19.431973 Date: 2021-02-19 Source: bioRxiv

    The COVID-19 pandemic MESHD, caused by the SARS-CoV-2 virus, has a huge impact on the world. Although several vaccines have recently reached the market, the development of specific antiviral drugs against SARS-CoV-2 is an important additional strategy in fighting the pandemic. One of the most promising pharmacological targets is the viral main protease PROTEIN ( Mpro PROTEIN). Here, we present an optimized biochemical assay procedure for SARS-CoV-2 Mpro PROTEIN. We have comprehensively investigated the influence of different buffer components and conditions on the assay performance, and characterized six FRET substrates with a 2-Abz/Tyr(3-NO2) FRET pair. The substrates 2-AbzSAVLQSGTyr(3-NO2)R-OH, a truncated version of the established DABCYL/EDANS FRET substrate, and a new substrate 2-AbzVVTLQSGTyr(3-NO2)R-OH are promising candidates for screening and inhibitor characterization. In the latter substrate, the incorporation of Val at the position P5 improved the catalytic efficacy. Based on the obtained results, we present here a reproducible, reliable assay protocol using highly affordable buffer components.

    N-Terminal finger stabilizes the reversible feline drug GC376 in SARS-CoV-2 Mpro PROTEIN

    Authors: Elena Arutyunova; Muhammad Bashir Khan; Conrad Fischer; Jimmy Lu; Tess Lamer; Wayne Vuong; Marco J van Belkum; Ryan T McKay; D. Lorne Tyrrell; John C Vederas; Howard S Young; M Joanne Lemieux

    doi:10.1101/2021.02.16.431021 Date: 2021-02-16 Source: bioRxiv

    The main protease PROTEIN ( Mpro PROTEIN, also known as 3CL protease PROTEIN) of SARS-CoV-2 is a high priority drug target in the development of antivirals to combat COVID-19 MESHD infections. A feline coronavirus antiviral drug, GC376, has been shown to be effective in inhibiting the SARS-CoV-2 main protease PROTEIN and live virus growth. As this drug moves into clinical trials, further characterization of GC376 with the main protease PROTEIN of coronaviruses is required to gain insight into the drug's properties, such as reversibility and broad specificity. Reversibility is an important factor for therapeutic proteolytic inhibitors to prevent toxicity MESHD due to off-target effects. Here we demonstrate that GC376 has nanomolar Ki values with the Mpro from both SARS-CoV-2 PROTEIN and SARS-CoV strains. Restoring enzymatic activity after inhibition by GC376 demonstrates reversible binding with both proteases. In addition, the stability and thermodynamic parameters of both proteases were studied to shed light on physical chemical properties of these viral enzymes, revealing higher stability for SARS-CoV-2 Mpro PROTEIN. The comparison of a new X-ray crystal structure of Mpro PROTEIN from SARS-CoV MESHD complexed with GC376 reveals similar molecular mechanism of inhibition compared to SARS-CoV-2 Mpro PROTEIN, and gives insight into the broad specificity properties of this drug. In both structures, we observe domain swapping of the N-termini in the dimer of the Mpro PROTEIN, which facilitates coordination of the drug's P1 position. These results validate that GC376 is a drug with an off-rate suitable for clinical trials.

    Liquiritin from Glycirrhyza Glabra L (Fabaceae) - a Natural Derived Drug, as a Potential Inhibitor for SARS-CoV-2

    Authors: Akash Vanzara; Ravi Patel; Amisha Patel; Nimisha Patel; Kapil Yadav; Padamnabhi Nagar

    doi:10.26434/chemrxiv.13853345.v1 Date: 2021-02-16 Source: ChemRxiv

    Novel Corona virus-2 ( Covid-19 MESHD) is spreading and causing major damage around the globe and constantly increasing daily. There is a prerequisite of expeditious development of safe and efficient drugs for such a contagious disease. In this regard, utilization of a computational approach with an aim to provide potential enzyme inhibitors derived from natural resources will give a providential therapy. The present study investigated one of the promising plants namely Glycyrrhiza glabra L. It has various medicinal properties viz. anti-inflammatory, anti- cancer MESHD, anti-demulcent, expectorant, etc. In-Silico Analysis of liquiritin against SARS-CoV-2 Mpro PROTEIN was carried out using Autodock 4.2.6 and results were compared with presently prescribed drugs i.e. dexamethasone, remdesivir, hydroxychloroquine, and azithromycin. The binding energy of liquiritin was found to be -6.62 kcal/mol. It shows presence of hydrogen bond, hydrophobic interaction and electrostatic interaction with six active residues THR26, GLY143, CYS145, HIS MESHD 164, GLU166, and GLN189. Comparative studies investigated that dexamethasone, remdesivir, hydroxychloroquine, and azithromycin have four (THR26, GLY143, CYS145, GLU166), three (CYS145, GLU166, GLN189), four (GLY143, CYS145, HIS MESHD 164, GLN189) and two (GLU166, GLN189) identical active residues, respectively. The present study recommended liquiritin as a potential candidate against SARS-CoV-2 as it is naturally derived and has tremendous traditional usage against various diseases. However, in-vitro and in-vivo studies are required to prove its efficacy.

    ALG-097111, a potent and selective SARS-CoV-2 3-chymotrypsin- like cysteine protease PROTEIN inhibitor exhibits in vivo efficacy in a Syrian Hamster model

    Authors: Koen Vandyck; Rana Abdelnabi; Kusum Gupta; Dirk Jochmans; Andreas Jekle; Jerome Deval; Dinah Misner; Dorothée Bardiot; Caroline S. Foo; Cheng Liu; Suping Ren; Leonid Beigelman; Lawrence M. Blatt; Sandro Boland; Laura Vangeel; Steven Dejonghe; Patrick Chaltin; Arnaud Marchand; Vladimir Serebryany; Antitsa Stoycheva; Sushmita Chanda; Julian A. Symons; Pierre Raboisson; Johan Neyts

    doi:10.1101/2021.02.14.431129 Date: 2021-02-15 Source: bioRxiv

    There is an urgent need for antivirals targeting the SARS-CoV-2 virus to fight the current COVID-19 pandemic MESHD. The SARS-CoV-2 main protease PROTEIN ( 3CLpro PROTEIN) represents a promising target for antiviral therapy. The lack of selectivity for some of the reported 3CLpro PROTEIN inhibitors, specifically versus cathepsin L, raises potential safety and efficacy concerns. ALG-097111 potently inhibited SARS-CoV-2 3CLpro PROTEIN (IC50 = 7 nM) without affecting the activity of human cathepsin L HGNC (IC50 > 10 M). When ALG-097111 was dosed in hamsters challenged with SARS-CoV-2, a robust and significant 3.5 log10 (RNA copies/mg) reduction of the viral RNA copies and 3.7 log10 (TCID50/mg) reduction in the infectious virus titers in the lungs was observed. These results provide the first in vivo validation for the SARS-CoV-2 3CLpro PROTEIN as a promising therapeutic target for selective small molecule inhibitors.

    Potent, Novel SARS-CoV-2 PLpro PROTEIN Inhibitors Block Viral Replication in Monkey and Human Cell Cultures

    Authors: Zhengnan Shen; Kiira Ratia; Laura Cooper; Deyu Kong; Hyun Lee; Youngjin Kwon; Yangfeng Li; Saad Alqarni; Fei Huang; Oleksii Dubrovskyi; Lijun Rong; Gregory RJ Thatcher; RUI XIONG

    doi:10.1101/2021.02.13.431008 Date: 2021-02-15 Source: bioRxiv

    Antiviral agents blocking SARS-CoV-2 viral replication are desperately needed to complement vaccination to end the COVID-19 pandemic MESHD. Viral replication and assembly are entirely dependent on two viral cysteine proteases: 3C-like protease ( 3CLpro PROTEIN) and the papain-like protease PROTEIN ( PLpro PROTEIN). PLpro PROTEIN also has deubiquitinase (DUB) activity, removing ubiquitin (Ub) and Ub-like modifications from host proteins, disrupting the host immune response. 3CLpro PROTEIN is inhibited by many known cysteine protease inhibitors, whereas PLpro PROTEIN is a relatively unusual cysteine protease, being resistant to blockade by such inhibitors. A high-throughput screen of biased and unbiased libraries gave a low hit rate, identifying only CPI-169 and the positive control, GRL0617, as inhibitors with good potency (IC50 < 10 lower case Greek M). Analogues of both inhibitors were designed to develop structure-activity relationships; however, without a co-crystal structure of the CPI-169 series, we focused on GRL0617 as a starting point for structure-based drug design, obtaining several co-crystal structures to guide optimization. A series of novel 2-phenylthiophene-based non-covalent SARS-CoV-2 PLpro PROTEIN inhibitors were obtained, culminating in low nanomolar potency. The high potency and slow inhibitor off-rate were rationalized by newly identified ligand interactions with a ' BL2 HGNC groove' that is distal from the active site cysteine. Trapping of the conformationally flexible BL2 HGNC loop by these inhibitors blocks binding of viral and host protein substrates; however, until now it has not been demonstrated that this mechanism can induce potent and efficacious antiviral activity. In this study, we report that novel PLpro PROTEIN inhibitors have excellent antiviral efficacy and potency against infectious SARS-CoV-2 replication in cell cultures. Together, our data provide structural insights into the design of potent PLpro PROTEIN inhibitors and the first validation that non-covalent inhibitors of SARS-CoV-2 PLpro PROTEIN can block infection of human cells with low micromolar potency.

    Benchmarking Deep Graph Generative Models for Optimizing New Drug Molecules for COVID-19 MESHD

    Authors: Logan Ward; Jenna A. Bilbrey; Sutanay Choudhury; Neeraj Kumar; Ganesh Sivaraman

    id:2102.04977v1 Date: 2021-02-09 Source: arXiv

    Design of new drug compounds with target properties is a key area of research in generative modeling. We present a small drug molecule design pipeline based on graph-generative models and a comparison study of two state-of-the-art graph generative models for designing COVID-19 MESHD targeted drug candidates: 1) a variational autoencoder-based approach (VAE) that uses prior knowledge of molecules that have been shown to be effective for earlier coronavirus treatments and 2) a deep Q-learning method (DQN) that generates optimized molecules without any proximity constraints. We evaluate the novelty of the automated molecule generation approaches by validating the candidate molecules with drug-protein binding affinity models. The VAE method produced two novel molecules with similar structures to the antiretroviral protease inhibitor Indinavir that show potential binding affinity for the SARS-CoV-2 protein target 3-chymotrypsin-like protease (3CL PROTEIN-protease).

    Post-infection treatment with a protease inhibitor increases survival of mice with a fatal SARS-CoV-2 infection MESHD

    Authors: Chamandi Dampalla; Jian Zheng; Krishani Perera; Lok Yin Roy Wong; David Meyerholz; Harry Nguyen; Maithri Kashipathy; Kevin Battaile; Scott Lovell; Yunjeong Kim; Stanley Perlman; William Groutas; Kyeong-Ok Chang

    doi:10.1101/2021.02.05.429937 Date: 2021-02-05 Source: bioRxiv

    Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection continues to be a serious global public health threat. The 3C-like protease ( 3CLpro PROTEIN) is a virus protease encoded by SARS-CoV-2, which is essential for virus replication. We have previously reported a series of small molecule 3CLpro PROTEIN inhibitors effective for inhibiting replication of human coronaviruses including SARS-CoV-2 in cell culture and in animal models. Here we generated a series of deuterated variants of a 3CLpro PROTEIN inhibitor, GC376, and evaluated the antiviral effect against SARS-CoV-2. The deuterated GC376 displayed potent inhibitory activity against SARS-CoV-2 in the enzyme and the cell-based assays. The K18- hACE2 HGNC mice develop mild to lethal infection commensurate with SARS-CoV-2 challenge doses and was proposed as a model for efficacy testing of antiviral agents. We treated lethally infected mice with a deuterated derivative of GC376. Treatment of K18- hACE2 HGNC mice at 24 hr post infection with a derivative (compound 2) resulted in increased survival of mice compared to vehicle-treated mice. Lung virus titers were decreased, and histopathological changes were ameliorated in compound 2-treated mice compared to vehicle-treated mice. Structural investigation using high-resolution crystallography illuminated binding interactions of 3CLpro PROTEIN of SARS-CoV-2 and SARS-CoV MESHD with deuterated variants of GC376. Taken together, deuterated GC376 variants have excellent potential as antiviral agents against SARS-CoV-2.

    Metal Complexes of Tridentate Schiff Base: Synthesis, Characterization, Biological Activity and Molecular Docking Studies with COVID-19 MESHD Protein Receptor

    Authors: mohamed m Omar; Walaa H. Mahmoud; Yasmin mamdoh hussien Ahmed; Gehad G. Mohamed

    doi:10.21203/ Date: 2021-02-04 Source: ResearchSquare

    Mononuclear chelates of Cr(III), Mn(II), Fe(III), Ni(II), Cu(II), Zn(II) and Cd(II) resulting from new tridentate Schiff base ligand, 4-((1-(5-acetyl-2,4-dihydroxyphenyl)ethylidene)amino)-1,5-dimethyl-2-phenyl-1H-pyrazol-3(2H)-one, were synthesized and characterized via various spectroscopic methods. Metal to ligand ratio was found to be 1:1, which was revealed via elemental analysis. IR has sharp out that the coordination of the ligand towards the metal ions was carried out via NOO atoms. UV-Vis, 1HNMR spectral data, molar conductance measurements, BET HGNC surface area, melting points and theoretically through density function theory were used such as characterizing techniques in supporting of further interpretation of the complexes structures. The complexes were octahedral except Cu(II) and Ni(II) complexes were tetrahedral as suggested through the magnetic moment measurement. The complexes were found to have surface area, pore volume and particle radius 23–176 m2 g− 1, 0.02–0.33 cc/g and 8.71–4.32 nm, respectively, as pointed out from BET HGNC measurement. Schiff base ligand and its metal complexes were tested in vitro to estimate their bactericidal activity opposed to Gram-negative and Gram-positive bacteria and antifungal organisms. In the recent incident of a novel coronavirus (SARS-CoV-2) spreads, antiviral drug detection is of most importance. MOE 2008 was used headed for screen potential drugs with molecular docking by the structural protein and non-structural protein sites of new coronavirus and the study was constructed to molecular docking without validation through MD simulations. Interactions with the main protease PROTEIN may play a key role in fighting against viruses.

    Identification of the Potential Hits for Hindering Interaction of SARS-CoV-2 Main Protease PROTEIN (M pro ) from the Pool of Antiviral Phytochemicals utilizing Molecular Docking and Molecular Dynamics ( MD MESHD) Simulations

    Authors: Chirag N. Patel; Dharmesh G. Jaiswal; Siddhi P. Jani; Naman Mangukia; Robin M. Parmar; Himanshu A. Pandya

    doi:10.21203/ Date: 2021-01-30 Source: ResearchSquare

    The novel SARS-CoV-2 is an etiological factor that triggers Coronavirus disease MESHD in 2019 ( COVID-19 MESHD) and tends to be an imminent occurrence of a pandemic. Out of all recognized solved complexes linked to SARS-CoV MESHD, Main protease PROTEIN ( Mpro PROTEIN) is considered a desirable antiviral phytochemical that play a crucial role in virus assembly and possibly non-interactive capacity to adhere to any viral host protein. In this research, SARS-CoV-2 MPro was chosen as a focus for the detection of possible inhibitors using a variety of different analytical methods such as molecular docking, ADMET analysis, dynamic simulations and binding free energy measurements. Virtual screening of known natural compounds recognized Withanoside V, Withanoside VI, Racemoside B, Racemoside A and Shatavarin IX as future inhibitors of SARS-CoV-2 MPro with stronger energy binding. Also, simulations of molecular dynamics for a 100 ns time scale showed that much of the main SARS-CoV-2 MPro interactions had been maintained in the simulation routes. Binding free energy calculations using the MM/PBSA method ranked the top five possible natural compounds that can act as effective SARS-CoV-2 MPro inhibitors.

    High-Resolution Mining of SARS-CoV-2 Main Protease PROTEIN Conformational Space: Supercomputer-Driven Unsupervised Adaptive Sampling

    Authors: Theo Jaffrelot Inizan; Frédéric Célerse; Olivier Adjoua; Dina El Ahdab; Luc-Henri Jolly; Chengwen Liu; Pengyu Ren; Matthieu Montes; Nathalie Lagarde; Louis Lagardère; Pierre Monmarché; Jean-Philip Piquemal

    doi:10.26434/chemrxiv.13003166.v6 Date: 2021-01-28 Source: ChemRxiv

    We provide a new unsupervised adaptive sampling strategy capable of producing microsecondtimescale molecular dynamics ( MD MESHD) simulations using many-body polarizable force fields (PFF) on modern supercomputers. The global exploration problem is decomposed into a set of separate MD trajectories that can be restarted within an iterative/selective process to achieve sufficient phase-space sampling within large biosystems, while accurate statistical properties can be obtained through debiasing. With this pleasingly parallel setup, the Tinker-HP package can be powered by an arbitrary large number of GPUs (Graphics Processing Unit) cards available on pre-exascale supercomputers, reducing to days explorations that would have taken years. We applied the approach to the urgent problem of the modeling of the SARS–CoV–2 Main protease PROTEIN ( Mpro PROTEIN) dimer. A 15.14 microsecond high-resolution all-atom simulation (AMOEBA PFF) of its apo state is provided and compared to other available long-timescale non-PFF data. Noticeable differences are found between clustering analysis of the simulations, the AMOEBA adaptive results exhibiting a richer conformational space. Overall, our high-resolution AMOEBA structural analysis captures key experimental observations concerning the stability of the oxyanion hole, a marker of activity through the stability of different stacking and salt bridge interactions. A dissymmetry is found between the enzyme protomers that exhibit different volumes. One of them appears fully inactive while the other is "activable", exhibiting some partial activity features. This activity evaluation can be further traced back to the large flexibility of the C terminal domain, fully captured by AMOEBA but not seen in X-rays due to insufficient MESHD electron densities related to the domain high mobility. The C–terminal region of the fully inactive protomer is shown to oscillate between several states, one of them interacting with the other protomer active site, therefore potentially modulating down its activity. Overall, these results reinforce the experimental hypothesis of a full inactivation of the apo state and clearly capture the asymmetric nature of protomers. Additional analysis show that the cavities volumes of the active and distal sites are found to be larger in the most active protomer with AMOEBA. To a larger extend, the PFF finds significantly larger cavities than those obtained with classical, non-polarizable simulations. The consequences on druggability are discussed as additional potential druggable cryptic pockets are found. All data produced within this research are fully accessible to the community for further analysis.

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins

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