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    Structural dynamics of the β-coronavirus Mpro PROTEIN protease ligand binding sites

    Authors: Eunice Cho; Margarida Rosa; Ruhi Anjum; Saman Mehmood; Mariya Soban; Moniza Mujtaba; Khair Bux; Sarath Chandra Dantu; Alessandro Pandini; Junqi Yin; Heng Ma; Arvind Ramanathan; Barira Islam; Antonia Mey; DEBSINDHU BHOWMIK; Shozeb Haider

    doi:10.1101/2021.03.31.437918 Date: 2021-04-01 Source: bioRxiv

    {beta}-coronaviruses alone have been responsible for three major global outbreaks in the 21st century. The current crisis has led to an urgent requirement to develop therapeutics. Even though a number of vaccines are available, alternative strategies targeting essential viral components are required as a back-up against the emergence of lethal viral variants. One such target is the main protease PROTEIN ( Mpro PROTEIN) that plays an indispensible role in viral replication. The availability of over 270 Mpro PROTEIN X-ray structures in complex with inhibitors provides unique insights into ligand-protein interactions. Herein, we provide a comprehensive comparison of all non-redundant ligand-binding sites available for SARS-CoV2, SARS-CoV MESHD and MERS-CoV Mpro PROTEIN. Extensive adaptive sampling has been used to explore conformational dynamics employing convolutional variational auto encoder-based deep learning, and investigates structural conservation of the ligand binding sites using Markov state models across {beta}-coronavirus homologs. Our results indicate that not all ligand-binding sites are dynamically conserved despite high sequence and structural conservation across {beta}-coronavirus homologs. This highlights the complexity in targeting all three Mpro PROTEIN enzymes with a single pan inhibitor.

    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.

    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.

    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.

    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.

    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.

    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.

    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.

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins

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