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    SARS-CoV-2 Nsp5 HGNC Protein Causes Acute Lung Inflammation MESHD: A Dynamical Mathematical Model

    Authors: José Díaz; Elena R. Álvarez-Buylla; Antonio Bensussen

    id:10.20944/preprints202012.0749.v2 Date: 2021-03-15 Source: Preprints.org

    In the present work we propose a dynamical mathematical model of the lung cells inflammation process MESHD in response to SARS-CoV-2 infection MESHD. In this scenario the main protease PROTEIN Nsp5 HGNC enhances the inflammatory process, increasing the levels of NF kB, IL-6 HGNC, Cox2 HGNC, and PGE2 with respect to a reference state without the virus. In presence of the virus the translation rates of NF kB and IkB arise to a high constant value, and when the translation rate of IL-6 HGNC also increases above the threshold value of 7 pg mL-1 s-1 the model predicts a persistent over stimulated immune state with high levels of the cytokine IL-6 HGNC. Our model shows how such over stimulated immune state becomes autonomous of the signals from other immune cells such as macrophages and lymphocytes, and does not shut down by itself. We also show that in the context of the dynamical model presented here, Dexamethasone or Nimesulide have little effect on such inflammation MESHD state of the infected lung cell, and the only form to suppress it is with the inhibition of the activity of the viral protein Nsp5 HGNC.To that end, our model suggest that drugs like Saquinavir may be useful. In this form, our model suggests that Nsp5 HGNC is effectively a central node underlying the severe acute lung inflammation MESHD during SARS-CoV-2 infection MESHD. The persistent production of IL-6 HGNC by lung cells can be one of the causes of the cytokine storm observed in critical patients with COVID19 MESHD. Nsp5 HGNC seems to be the switch to start inflammation MESHD, the consequent overproduction of the ACE2 HGNC receptor, and an important underlying cause of the most severe cases of COVID19 MESHD.

    Unravelling Vitamins as Wonder Molecules for Covid-19 MESHD Management via Structure-based Virtual Screening

    Authors: Medha Pandya; Sejal Shah; Dhanalakshmi Menamadathil; Ayushman Gadnayak; Tanzil Juneja; Amisha Patel; Kajari Das; Jayashankar Das

    doi:10.21203/rs.3.rs-144177/v1 Date: 2021-01-09 Source: ResearchSquare

    The emergence situation of coronavirus disease 2019 MESHD ( COVID-19 MESHD) pandemic has realised the global scientific communities to develop strategies for immediate priorities and long-term approaches for utilization of existing knowledge and resources which can be diverted to pandemic preparedness planning. Lack of proper vaccine candidate and therapeutic management has accelerated the researchers to repurpose the existing drugs with known preclinical and toxicity MESHD profiles, which can easily enter Phase 3 or 4 or can be used directly in clinical settings. We focused to justify even exploration of supplements, nutrients and vitamins to dampen the disease burden of the current pandemic may play a crucial role for its management. We have explored structure based virtual screening of 15 vitamins against non-structural ( NSP3 HGNC NSP3 PROTEIN, NSP5 PROTEIN NSP5 HGNC, ORF7a PROTEIN, NSP12 PROTEIN, ORF3a PROTEIN), structural (Spike & Hemagglutinin esterase) and host protein furin HGNC. The in silico analysis exhibited that vitamin B12, Vitamin B9, Vitamin D3 determined suitable binding while vitamin B15 manifested remarkable H-bond interactions with all targets. Vitamin B12 bestowed the lowest energies with human furin HGNC and SARS-COV-2 RNA dependent RNA polymerase PROTEIN. Furin HGNC mediated cleavage of the viral spike glycoprotein PROTEIN is directly related to enhanced virulence of SARS-CoV-2. In contrast to these, vitamin B12 showed zero affinity with SARS-CoV-2 spike PROTEIN protein. These upshots intimate that Vitamin B12 could be the wonder molecule to shrink the virulence by hindering the furin HGNC mediated entry of spike to host cell. These identified molecules may effectively assist in SARS-CoV-2 therapeutic management to boost the immunity by inhibiting the virus imparting relief in lung inflammation MESHD.

    The repurposed drugs suramin and quinacrine inhibit cooperatively in vitro SARS-CoV-2 3CLpro PROTEIN

    Authors: Raphael J Eberle; Danilo S Olivier; Marcos S Amaral; Dieter Willbold; Raghuvir K Arni; Monika A Coronado; Andrea Benedetti; Jan Larmann; Markus A Weigand; Sean McGrath; Claudia Denkinger; Stefan Baral; Jeff Kwong; Deepali Kumar; Atul Humar; Adrienne Chan; Seham Noureldin; Joshua Booth; Rachel Hong; David Smookler; Wesam Aleyadeh; Anjali Patel; Bethany Barber; Julia Casey; Ryan Hiebert; Henna Mistry; Ingrid Choong; Colin Hislop; Deanna Santer; D. Lorne Tyrrell; Jeffrey S. Glenn; Adam J. Gehring; Harry LA Janssen; Bettina Hansen

    doi:10.1101/2020.11.11.378018 Date: 2020-11-12 Source: bioRxiv

    Since the first report of a new pneumonia disease MESHD in December 2019 (Wuhan, China) up to now WHO reported more than 50 million confirmed cases and more than one million losses, globally. The causative agent of COVID-19 MESHD (SARS-CoV-2) has spread worldwide resulting in a pandemic of unprecedented magnitude. To date, no clinically safe drug or vaccine is available and the development of molecules to combat SARS-CoV-2 infections MESHD is imminent. A well-known strategy to identify molecules with inhibitory potential against SARS-CoV-2 proteins is the repurposing of clinically developed drugs, e.g., anti-parasitic drugs. The results described in this study demonstrate the inhibitory potential of quinacrine and suramin against SARS-CoV-2 main protease PROTEIN ( 3CLpro PROTEIN). Quinacrine and suramin molecules present a competitive and non-competitive mode of inhibition, respectively, with IC50 and KD values in low M range. Using docking and molecular dynamics simulations we identified a possible binding mode and the amino acids involved in these interactions. Our results suggested that suramin in combination with quinacrine showed promising synergistic efficacy to inhibit SARS-CoV-2 3CLpro PROTEIN. The identification of effective, synergistic drug combinations could lead to the design of better treatments for the COVID-19 MESHD disease. Drug repositioning offers hope to the SARS-CoV-2 control.

    Duple extinguishment of COVID-19 MESHD: single compound synergized inhibition of SARS-CoV-2 replication and direct suppression of inflammatory cytokines in vitro/vivo

    Authors: Xueyun Gao; Yong Gong; Wenjie Tan; Huaidong Jiang; Jianxun Qi; Jincun Zhao; Bo Sun; Xingfa Gao; Xuejiao Gao; Peng Cao; Bo He; Jiadong Fan; Yuhui Dong; Fuping Gao; Qing Yuan; Yucong Gao; Wencong Zhao; Chunyu Zhang; Zhongying Du; Fei Ye; Zhesheng He; Timothy H. Burgess; Christopher C. Broder; Graham Lord; Timothy Felton; Chris Brightling; Ling-Pei Ho; - NIHR Respiratory TRC; - CIRCO; Karen Piper Hanley; Angela Simpson; John R Grainger; Tracy Hussell; Elizabeth R Mann

    doi:10.1101/2020.10.16.342097 Date: 2020-10-16 Source: bioRxiv

    The virus replication and lung inflammation MESHD are basic targets for COVID-19 MESHD treatment. To effectively treat COVID-19 MESHD, the best chemical drug should combine inhibition of SARS-CoV-2 replication and direct suppression of inflammatory cytokine expression together. Our SARS-CoV-2 main protease PROTEIN ( Mpro PROTEIN) crystal structure studies revealed Au(I), derived from auranofin (AF) or gold cluster (GA), could specifically bind thiolate of Cys145 of SARS-CoV-2 Mpro PROTEIN. GA or AF could well inhibit Mpro PROTEIN activity and significantly decrease SARS-CoV-2 replication in cell. Cell studies showed that either AF or GA could down-regulate NF{kappa}B pathway, therefore significantly inhibit inflammatory cytokine level of IL-6, IL-1{beta}, TNF- in macrophage and bronchial epithelial cell, respectively. The lung viral load in GA treated COVID-19 MESHD mice (15mg/kg.bw) is significantly lower than that in normal saline (NS, 0.9% NaCl) treated COVID-19 MESHD mice, and pathological studies revealed GA treatment (score ~1.8) significantly reduced lung inflammatory injury MESHD compared with NS treated COVID-19 MESHD mice (score ~3). After normal mice were treated by GA (15mg/kg), the Au ingredient well distributed into lungs and there are no pathological changes in main organs when compared with control mice. The toxicity MESHD results revealed GA is more safety than auranofin for cell/mice/rat. The rat pharmacokinetics studies show GA is with high bioavailability (> 90%) in vivo.

    In Silico Mutagenesis Based Remodeling of SARs-CoV-1 Peptide (ATLQAIAS) to Inhibit SARs-CoV-2: Structural-dynamics and Free Energy Calculations

    Authors: Abbas Khan; Shaheena Umbreen; Asma Hameed; Rida Fatima; Ujala Zahoor; Zainib Babar; Muhammad Waseem; Zahid Hussain; Muhammad Rizwan; Nasib Zaman; Shahid Ali; Muhammad Suleman; Abdullah Shah; Liaqat Ali; Syed Shujait Ali; Dong-Qing Wei

    doi:10.21203/rs.3.rs-76731/v1 Date: 2020-09-12 Source: ResearchSquare

    Background:The prolific spread of COVID-19 MESHD caused by a novel coronavirus (SARS-CoV-2) from its epicenter in Wuhan, China, to every nook and cranny of the world after December 2019, jeopardize the prevailing health system in the world and has raised serious concerns about human safety. To date efforts are continuing to design small molecule inhibitor, vaccines and many other therapeutic options are practiced but their final therapeutic potential is still to be tested. Using the old drug or vaccine or peptides could aid this process to avoid such long experimental procedure. Results:Hence, here we have repurposed a small peptide (ATLQAIAS) from the previous study which reported the inhibitory effects of this peptide. We used in silico mutagenesis approach to design more peptides from the native wild peptide, which revealed that substitutions (T2W, T2Y, L3R and A5W) could increase the binding affinity of the peptide towards the 3CLpro PROTEIN. Furthermore, using MD simulation and free energy calculation confirmed its dynamics stability and stronger binding affinities. Per-residues energy decomposition analysis revealed that the specified substitution significantly increased the binding affinity at residue level. Conclusion:Our wide-ranging analyses of binding affinities disclosed that our designed peptide owns the potential to hinder the SARS-CoV-2 and will reduce the progression of SARs-CoV-2-borne pneumonia MESHD. Our analysis strongly suggests the experimental and clinical validation of these peptides to curtail the recent corona outbreak.

    Repurposing Simeprevir, Calpain Inhibitor IV and a Cathepsin F Inhibitor Against SARS-CoV-2: A Study Using in Silico Pharmacophore Modeling and Docking Methods

    Authors: Abhithaj J; Dileep Francis; Sharanya C.S; arun kumar; Sadasivan C; Jayadevi Variyar

    doi:10.26434/chemrxiv.12317213.v1 Date: 2020-05-18 Source: ChemRxiv

    The world has come to a sudden halt due to the incessant spread of a viral pneumonia MESHD dubbed COVID-19 MESHD caused by the beta-coronavirus, SARS-CoV-2. The pandemic spread of the virus has already claimed lakhs of valuable lives and has infected millions of people across the globe. The situation is further worsened by the fact that there is no approved therapeutics currently available for the treatment of the disease. The only way to handle the crisis is the rapid development of a therapeutic strategy to combat the virus. Computational biology offers resources to rapidly identify novel drug leads and to repurpose existing drugs at the expense of minimal resources and time. The main protease PROTEIN of SARS-CoV-2 is key to the replication and propogation of the virus in the host cells. Inhibiting the protease blocks replication and hence is an attractive therapeutic target in the virus. The crystal structures of the protein in complex with inhibitors are available in public databases. Here we describe the screening of the DrugBank database, a public repository for small molecule therapeutics, to identify approved or experimental phase drugs that can be repurposed against the main protease PROTEIN of SARS-CoV2. The initial screening was performed on more than 13,000 drug entries in the target database using an energy optimised pharmacophore hypothesis AARRR. A sub-set of the molecules selected based on the fitness score was further screened using molecular docking by sequentially filtering the molecules through the high throughput virtual screening, extra precision and standard precision docking modalities. The most promising hits were subjected to binding free energy estimation using the MMGBSA method. Approved drugs viz, Cobicistat, Larotrectinib and Simeprevir were identified as potential candidates for repurposing. Drugs in the discovery phase identified as inhibitors include the known cysteine protease inhibitors, Calpain inhibitor IV and an experimental cathepsin F inhibitor.

    In silico drug designing for COVID-19 MESHD: an approach of highthroughput virtual screening, molecular and essential dynamics simulations

    Authors: Rakesh Kumar; Rahul Kumar; Pranay Tanwar

    doi:10.21203/rs.3.rs-28221/v1 Date: 2020-05-10 Source: ResearchSquare

    SARS-CoV2, a new coronavirus has emerged in Wuhan city of China, December last year causing pneumonia MESHD named COVID-19 MESHD which has now spread to entire world. By April 2020, number of confirmed cumulative cases crossed ~2.4 million worldwide, according to WHO. Till date, no effective treatment or drug is available for this virus. Availability of X-ray structures of SARS-CoV2 main protease PROTEIN ( Mpro PROTEIN) provided the potential opportunity for structure based drug designing. Here, we have made an attempt to do computational drug design by targeting main protease PROTEIN of SARS-CoV2. Highthroughput virtual screening of million molecules and natural compounds databases was performed followed by docking. Six ligands showed better binding affinities which were further optimized by MD simulation and rescoring of binding energy was calculated through MM/PBSA method. In addition, conformational effect of various ligands on protein was examined through essential dynamics simulation. Three compounds namely ZINC14732869, ZINC19774413 and ZINC19774479 were finally filtered that displayed high binding free energies than N3 inhibitor and form conformationally stable complex. Hence, current study features the discovery of novel inhibitors for main protease PROTEIN of CoV2 which will provide effective therapeutic candidates against COVID19 MESHD.

    Identification of Potential Drug Targets and Prediction of the Potential Impact of High Risk Non Synonymous Single Nucleotide Polymorphism in SARS-CoV-2 3C like Proteinase ( 3CLpro PROTEIN): A Computational Approach

    Authors: Sahar Elbager; abdelrahman hamza; Afra M. Al Bkrye; Asia M. Alrashied; Entisar N. M. Ali; Hadeel A. Mohamed; Hazem A. Abubaker; Israa A. Mohamed; Manal A. H. Goda; Mohammed Y. Basher; Naglla F.A. Gabir; Safinaz I. Khalil

    doi:10.26434/chemrxiv.12235181.v1 Date: 2020-05-05 Source: ChemRxiv

    On January 2020, a new coronavirus (officially named SARS-CoV-2) was associated with alarming outbreak of a pneumonia MESHD-like illness, which was later named by the WHO as COVID-19 MESHD, originating from Wuhan City, China. Although many clinical studies involving antiviral and immunomodulatory drug treatments for SARS-CoV-2 all without reported results, no approved drugs have been found to effectively inhibit the virus so far. Full genome sequencing of the virus was done, and uploaded to be freely available for the world scientists to explore. A promising target for SARS-CoV-2 drug design is a chymotrypsin- like cysteine protease PROTEIN ( 3CLpro PROTEIN), a main protease PROTEIN responsible for the replication and maturation of functional proteins in the life cycle of the SARS coronavirus. Here we aim to explore SARS-CoV-2 3CLpro PROTEIN as possible drug targets based on ligand- protein interactions. In addition, ADME properties of the ligands were also analyzed to predict their drug likeliness. The results revealed Out of 9 ligands, 8 ligands (JFM, X77, RZG, HWH, T8A, 0EN, PEPTIDE and DMS) showed best ADME properties. These findings suggest that these ligands can be used as potential molecules for developing potent inhibitors against SARS-CoV-2 3CLpro PROTEIN, which could be helpful in inhibiting the propagation of the COVID-19 MESHD. Furthermore, 10 potential amino acids residues were recognized as potential drug binding site (THR25, HIS41, GLY143, SER144, CYS145, MET165, GLU166, GLN189, ASP295 and ARG298). All those amino acid residues were subjected to missense SNP analysis were recognized to affect the structure and function of the protein. These characteristics provide them the promising to be target sites for the fresh generation inhibitors to work with and overcome drug resistance. These findings would be beneficial for the drug development for inhibiting SARS-CoV-2 3CLpro PROTEIN hence assisting the pharmacogenomics effort to manage the infection. of SARS-CoV-2.

    Structure-based drug design, virtual screening and high-throughput screening rapidly identify antiviral leads targeting COVID-19 MESHD

    Authors: Zhenming Jin; Xiaoyu Du; Yechun Xu; Yongqiang Deng; Meiqin Liu; Yao Zhao; Bing Zhang; Xiaofeng Li; Leike Zhang; Chao Peng; Yinkai Duan; Jing Yu; Lin Wang; Kailin Yang; Fengjiang Liu; Rendi Jiang; Xinglou Yang; Tian You; Xiaoce Liu; Xiuna Yang; Fang Bai; Hong Liu; Xiang Liu; Luke W. Guddat; Wenqing Xu; Gengfu Xiao; Chengfeng Qin; Zhengli Shi; Hualiang Jiang; Zihe Rao; Haitao Yang

    doi:10.1101/2020.02.26.964882 Date: 2020-02-27 Source: bioRxiv

    A new coronavirus (CoV) identified as COVID-19 MESHD virus is the etiological agent responsible for the 2019-2020 viral pneumonia MESHD outbreak that commenced in Wuhan1-4. Currently there is no targeted therapeutics and effective treatment options remain very limited. In order to rapidly discover lead compounds for clinical use, we initiated a program of combined structure-assisted drug design, virtual drug screening and high-throughput screening to identify new drug leads that target the COVID-19 MESHD virus main protease PROTEIN ( Mpro PROTEIN). Mpro PROTEIN is a key CoV enzyme, which plays a pivotal role in mediating viral replication and transcription, making it an attractive drug target for this virus5,6. Here, we identified a mechanism-based inhibitor, N3, by computer-aided drug design and subsequently determined the crystal structure of COVID-19 MESHD virus Mpro PROTEIN in complex with this compound. Next, through a combination of structure-based virtual and high-throughput screening, we assayed over 10,000 compounds including approved drugs, drug candidates in clinical trials, and other pharmacologically active compounds as inhibitors of Mpro PROTEIN. Six of these inhibit Mpro PROTEIN with IC50 values ranging from 0.67 to 21.4 M. Ebselen also exhibited promising antiviral activity in cell-based assays. Our results demonstrate the efficacy of this screening strategy, which can lead to the rapid discovery of drug leads with clinical potential in response to new infectious diseases where no specific drugs or vaccines are available.

    X-ray Structure of Main Protease PROTEIN of the Novel Coronavirus SARS-CoV-2 Enables Design of α-Ketoamide Inhibitors

    Authors: Linlin Zhang; Daizong Lin; Xinyuanyuan Sun; Katharina Rox; Rolf Hilgenfeld

    doi:10.1101/2020.02.17.952879 Date: 2020-02-20 Source: bioRxiv

    A novel coronavirus has been identified as the causative agent of a massive outbreak of atypical pneumonia MESHD originating at Wuhan, Hubei province, China. Involved in the formation of the coronavirus replication complex, the viral main protease PROTEIN ( Mpro PROTEIN, also called 3CLpro PROTEIN) represents an attractive target for therapy. We determined the crystal structure of the unliganded Mpro PROTEIN at 1.75 [A] resolution and used this structure to guide optimization of a series of alpha-ketoamide inhibitors. The main goal of the optimization efforts was improvement of the pharmacokinetic properties of the compounds. We further describe 1.95- and 2.20-[A] crystal structures of the complex between the enzyme and the most potent alpha-ketoamide optimized this way. These structures will form the basis for further development of these compounds to antiviral drugs.

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins

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