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    Identifying SARS-CoV-2 Antiviral Compounds by Screening for Small Molecule Inhibitors of nsp5 Main Protease PROTEIN

    Authors: Clovis Basier; Rupert Beale; Ganka Bineva-Todd; Berta Canal; Joseph F Curran; Tom D Deegan; John FX Diffley; Ryo Fujisawa; Michael Howell; Dhira Joshi; Karim Labib; Chew Theng Lim; Jennifer Milligan; Hema Nagaraj; George Papageorgiou; Christelle Soudy; Kang Wei Tan; Rachel Ulferts; Florian Weissmann; Mary Wu; Theresa U Zeisner

    doi:10.1101/2021.04.07.438806 Date: 2021-04-08 Source: bioRxiv

    The coronavirus 2019 ( COVID-19 MESHD) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 MESHD (SARS-CoV-2), spread around the world with unprecedented health and socio-economic effects for the global population. While different vaccines are now being made available, very few antiviral drugs have been approved. The main viral protease (nsp5) of SARS-CoV-2 provides an excellent target for antivirals, due to its essential and conserved function in the viral replication cycle. We have expressed, purified and developed assays for nsp5 protease activity. We screened the nsp5 protease against a custom chemical library of over 5,000 characterised pharmaceuticals. We identified calpain inhibitor I and three different peptidyl fluoromethylketones (FMK) as inhibitors of nsp5 activity in vitro, with IC50 values in the low micromolar range. By altering the sequence of our peptidomimetic FMK inhibitors to better mimic the substrate sequence of nsp5, we generated an inhibitor with a subnanomolar IC50. Calpain inhibitor I inhibited viral infection in monkey-derived Vero E6 cells, with an EC50 in the low micromolar range. The most potent and commercially available peptidyl-FMK compound inhibited viral growth in Vero E6 cells to some extent, while our custom peptidyl FMK inhibitor offered a marked antiviral improvement.

    High Throughput Virtual Screening and Validation of a SARS-CoV-2 Main Protease PROTEIN Non-Covalent Inhibitor

    Authors: Austin Clyde; Stephanie Galanie; Daniel W. Kneller; Heng Ma; Yadu Babuji; Ben Blaiszik; Alexander Brace; Thomas Brettin; Kyle Chard; Ryan Chard; Leighton Coates; Ian Foster; Darin Hauner; Vilmos Kertesz; Neeraj Kumar; Hyungro Lee; Zhuozhao Li; Andre Merzky; Jurgen G. Schmidt; Li Tan; Mikhail Titov; Anda Trifan; Matteo Turilli; Hubertus Van Dam; Srinivas C. Chennubhotla; Shantenu Jha; Andrey Kovalevsky; Arvind Ramanathan; Marti Head; Rick Stevens

    doi:10.1101/2021.03.27.437323 Date: 2021-03-27 Source: bioRxiv

    Despite the recent availability of vaccines against the acute respiratory syndrome coronavirus 2 MESHD (SARS-CoV-2), the search for inhibitory therapeutic agents has assumed importance especially in the context of emerging new viral variants. In this paper, we describe the discovery of a novel non-covalent small-molecule inhibitor, MCULE-5948770040, that binds to and inhibits the SARS-Cov-2 main protease PROTEIN ( Mpro PROTEIN) by employing a scalable high throughput virtual screening (HTVS) framework and a targeted compound library of over 6.5 million molecules that could be readily ordered and purchased. Our HTVS framework leverages the U.S. supercomputing infrastructure achieving nearly 91% resource utilization and nearly 126 million docking calculations per hour. Downstream biochemical assays validate this Mpro PROTEIN inhibitor with an inhibition constant (Ki) of 2.9 uM [95% CI 2.2, 4.0]. Further, using room-temperature X-ray crystallography, we show that MCULE-5948770040 binds to a cleft MESHD in the primary binding site of Mpro PROTEIN forming stable hydrogen bond and hydrophobic interactions. We then used multiple s-timescale molecular dynamics ( MD MESHD) simulations, and machine learning (ML) techniques to elucidate how the bound ligand alters the conformational states accessed by Mpro PROTEIN, involving motions both proximal and distal to the binding site. Together, our results demonstrate how MCULE-5948770040 inhibits Mpro PROTEIN and offers a springboard for further therapeutic design.

    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.

    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/rs.3.rs-191629/v1 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.

    Efficacy of GC-376 against SARS-CoV-2 virus infection MESHD in the K18 hACE2 HGNC transgenic mouse model

    Authors: C. Joaquin Caceres; Stivalis Cardenas-Garcia; Silvia Carnaccini; Brittany Seibert; Daniela S Rajao; Jun Wang; Daniel R Perez; Amanda J. Martinot; Cesar Piedra-Mora; Sidney Beecy; Sarah Ducat; Ronnie Chamanza; Sietske Rosendahl Huber; Leslie van der Fits; Erica N. Borducchi; Michelle Lifton; Jinyan Liu; Felix Nampanya; Shivani Patel; Lauren Peter; Lisa H. Tostanoski; Laurent Pessaint; Alex Van Ry; Brad Finneyfrock; Jason Velasco; Elyse Teow; Renita Brown; Anthony Cook; Hanne Andersen; Mark G. Lewis; Hanneke Schuitemaker; Dan H. Barouch; Christian Lavallee; Pierre-Olivier Hetu; Jean-Sebastien Paquette; Sylvie Levesque; Marieve Cossette; Anna Nozza; Malorie Chabot-Blanchet; Marie-Pierre Dube; Marie-Claude Guertin; Guy Boivin

    doi:10.1101/2021.01.27.428428 Date: 2021-01-27 Source: bioRxiv

    The COVID-19 pandemic MESHD caused by the Severe Acute Respiratory Syndrome Coronavirus-2 MESHD (SARS-CoV-2) is the defining global health emergency of this century. GC-376 is a Mpro PROTEIN inhibitor with antiviral activity against SARS-CoV-2 in vitro. Using the K18- hACE2 HGNC mouse model, the in vivo antiviral efficacy of GC-376 against SARS-CoV-2 was evaluated. GC-376 treatment was not toxic in K18- hACE2 HGNC mice and produced milder tissue lesions, reduced viral loads, fewer presence of viral antigen, and reduced inflammation MESHD in comparison to vehicle-treated controls, most notably in the brain in mice challenged with a low virus dose. Although GC-376 was not sufficient to improve neither clinical symptoms nor survival, it did show a positive effect against SARS-CoV-2 in vivo. This study supports the notion that the K18- hACE2 HGNC mouse model is suitable to study antiviral therapies against SARS-CoV-2, and GC-376 represents a promising lead candidate for further development to treat SARS-CoV-2 infection MESHD.

    Molecular Dynamics Reveals the Effects of Temperature on Critical SARS-CoV-2 Proteins MESHD

    Authors: Paul Morgan; Chih-Wen Shu

    doi:10.1101/2021.01.24.427990 Date: 2021-01-25 Source: bioRxiv

    Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a newly identified RNA virus that causes the serious infection Coronavirus Disease MESHD Coronavirus Disease 2019 MESHD ( COVID-19 MESHD). The incidence of COVID-19 MESHD is still increasing worldwide despite the summer heat and cool winter. However, little is known about seasonal stability of SARS-CoV-2. Herein, we employ Molecular Dynamics ( MD MESHD) simulations to explore the effect of temperature on four critical SARS-CoV-2 proteins. Our work demonstrates that the spike Receptor Binding Domain (RBD), Main protease PROTEIN ( Mpro PROTEIN), and nonstructural protein 3 (macro X) possesses extreme thermos-stability when subjected to temperature variations rendering them attractive drug targets. Furthermore, our findings suggest that these four proteins are well adapted to habitable temperatures on earth and are largely insensitive to cold and warm climates. Furthermore, we report that the critical residues in SARS-CoV-2 RBD MESHD were less responsive to temperature variations as compared to the critical residues in SARS-CoV MESHD. As such, extreme summer and winter climates, and the transition between the two seasons, are expected to have a negligible effect on the stability of SARS-CoV-2 which will marginally suppress transmission rates until effective therapeutics are available world-wide.

    Dimer-monomer equilibrium of SARS-CoV-2 main protease PROTEIN as affected by small molecule inhibitors: a biophysical investigation

    Authors: Lucia Silvestrini; Norhan Belhaj; Lucia Comez; Yuri Gerelli; Antonino Lauria; Valeria Libera; Paolo Mariani; Paola Marzullo; Maria Ortore; Antonio Palumbo Piccionello; Caterina Petrillo; Lucrezia Savini; Alessandro Paciaroni; Francesco Spinozzi

    doi:10.21203/rs.3.rs-135283/v1 Date: 2020-12-24 Source: ResearchSquare

    The maturation of coronavirus SARS-CoV-2 MESHD, which is the etiological agent at the origin of the COVID-19 pandemic MESHD, requires a main protease PROTEIN Mpro PROTEIN to cleave the virus-encoded polyproteins. Despite a wealth of experimental information already available, there is wide disagreement about the Mpro PROTEIN monomer-dimer equilibrium dissociation constant. Since the functional unit of Mpro PROTEIN is a homodimer, the detailed knowledge of the thermodynamics of this equilibrium is a key piece of information for possible therapeutic intervention, with small molecules interfering with dimerization being potential broad-spectrum antiviral drug leads. In the present study, we exploit small angle x-ray scattering ( SAXS MESHD) to investigate the structural features of the SARS-CoV-2 Mpro PROTEIN monomer-dimer equilibrium, by revealing the corresponding equilibrium dissociation constant and the associated thermodynamic parameters. SAXS MESHD is also used to study how the Mpro PROTEIN dissociation process is affected by small inhibitors selected through combinatorial design. Our results show that a clear picture connecting the ability of inhibitors to disrupt the Mpro PROTEIN dimerization with the loss of catalytic activity cannot be provided, thus highlighting the possible role of allosteric effects for the regulation of Mpro PROTEIN functionality.

    Glycyrrhizin effectively neutralizes SARS-CoV-2 in vitro by inhibiting the viral main protease PROTEIN

    Authors: Lukas van de Sand; Maren Bormann; Mira Alt; Leonie Schipper; Christiane Silke Heilingloh; Daniel Todt; Ulf Dittmer; Carina Elsner; Oliver Witzke; Adalbert Krawczyk

    doi:10.1101/2020.12.18.423104 Date: 2020-12-20 Source: bioRxiv

    The newly emerged coronavirus, which was designated as severe acute respiratory syndrome coronavirus 2 MESHD (SARS-CoV-2) is the causative agent of the COVID-19 MESHD disease. High effective and well-tolerated medication for hospitalized and non-hospitalized patients is urgently needed. Traditional herbal medicine substances were discussed as promising candidates for the complementary treatment of viral diseases MESHD and recently suggested for the treatment of COVID-19 MESHD. In the present study, we investigated aqueous licorice root extract for its neutralizing activity against SARS-CoV-2 in vitro, identified the active compound glycyrrhizin and uncovered the respective mechanism of viral neutralization. We demonstrated that glycyrrhizin, the primary active ingredient of the licorice root, potently neutralizes SARS-CoV-2 by inhibiting the viral main protease PROTEIN. Our experiments highlight glycyrrhizin as a potential antiviral compound that should be further investigated for the treatment of COVID-19 MESHD.

    Molecular Docking and Clinical Study of Inhibition of Phytochemical Compounds of Nigella Sativa, Matricaria Chamomilla and Origanum Vulgare L on COVID_19 Mpro PROTEIN

    Authors: Neda Shaghaghi; Sima Fereydooni; Naiemeh Molaei kordabad

    doi:10.26434/chemrxiv.13296524.v1 Date: 2020-12-01 Source: ChemRxiv

    Due to the high rate of infection reported in the new Coronavirus, in recent months, a lot of research has been done on the introduction of antiviral drugs. Recent studies have shown that inhibiting viral protease enzymes are highly effective in controlling infection caused by any type of virus. The aim of this study was to investigate the bioinformatics of inhibition of the new coronavirus protease enzyme by compounds in the essential oils of three medicinal plants. This is a descriptive-analytical study. For this bioinformatics analysis, the structure of compounds from PubChem database and the structure of COVID_19 protease enzyme were obtained from PDB database. Molecular docking was then performed by MVD software. The results showed that the site of interaction of the compounds in the protected area is enzymatic flap. Also, 15 patients voluntarily received steam therapy with the essential oils of these plants and their symptoms of lung infection MESHD improved. Therefore, it can be concluded that the studied compounds with strong interaction due to their natural origin and the possibility of less side effects, as well as their direct entry into the respiratory tract, these compounds are suitable for drug treatment for coronavirus infection MESHD.

    Naturally occurring phytochemical as inhibitors from Catharanthus roseus: An In-silico approaches for drug development against COVID-19 MESHD

    Authors: Rishee K. Kalaria; Hiren K. Patel

    doi:10.21203/rs.3.rs-116443/v1 Date: 2020-11-26 Source: ResearchSquare

    The current outbreak of the novel 2019 Coronavirus disease MESHD ( COVID-19 MESHD) is caused by SARS-CoV-2, has developed a threat to the world's human population. There are no effective therapies or vaccines yet, urging the serious efforts to tackle this pandemic situation. SARS-CoV-2 spike PROTEIN protein, papain like protease PROTEIN protein (PLPRO), main protease PROTEIN ( 3CLpro PROTEIN) and RNA dependent DNA polymerase are key factors in the virus infectious process and have been identified as potential targets for therapeutic formulation. Most people in India depend on conventional Indian medicine (phytochemical compounds) to treat diseases MESHD due to lower cost, easier accessibility and no adverse effects. A lot of studies have recently shown that phytochemicals contain an effective anti-viral activity. This study aims to investigate phytochemicals metabolites from the IMPPAT database (Indian Medicinal Plants Database) in order to identify potential COVID-19 MESHD inhibitors using in silico approaches. Certain phytochemical compounds with structure analogs like hydroxychloroquine and chloroquine from the IMPPAT database were taken for interaction with SARS-CoV-2 proteins MESHD. The Apparicine, 12-Chlorotabersonine, AC1NSULH and Vindolininol identified from Catharanthus roseus were further checked the ADMET property as well as ‘Lipinski’s rule and resulted in a strong binding affinity of (-7.6,-7.5) and (-7.6 -7.5) kcal/mol respectively for spikes and papain like protease PROTEIN protein of SARS-CoV-2. Our results indicate that these specific compounds can be used as effective inhibitors and help to pace up the drug development against SARS-CoV-2. Further investigation and testing of these inhibitors against SARS‐CoV‐2 are however required to check their clinical trial candidacy.

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SARS-CoV-2 Proteins


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