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      Structure-based drug repurposing for targeting Nsp9 replicase and spike proteins of severe acute respiratory syndrome coronavirus 2

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          Abstract

          Drug re-purposing might be a fast and efficient way of drug development against the novel coronavirus disease 2019 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We applied a bioinformatics approach using molecular dynamics and docking to identify FDA-approved drugs that can be re-purposed to potentially inhibit the non-structural protein 9 (Nsp9) replicase and spike proteins in SARS-CoV-2. We performed virtual screening of FDA-approved compounds, including antiviral, anti-malarial, anti-parasitic, anti-fungal, anti-tuberculosis, and active phytochemicals against the Nsp9 replicase and spike proteins. Selected hit compounds were identified based on their highest binding energy and favorable absorption, distribution, metabolism and excretion (ADME) profile. Conivaptan, an arginine vasopressin antagonist drug exhibited the highest binding energy (-8.4 Kcal/mol) and maximum stability with the amino acid residues present at the active site of the Nsp9 replicase. Tegobuvir, a non-nucleoside inhibitor of the hepatitis C virus, also exhibited maximum stability along with the highest binding energy (-8.1 Kcal/mol) at the active site of the spike proteins. Molecular docking scores were further validated by molecular dynamics using Schrodinger, which supported the strong stability of ligands with the proteins at their active sites through water bridges, hydrophobic interactions, and H-bonding. Our findings suggest Conivaptan and Tegobuvir as potential therapeutic agents against SARS-CoV-2. Further in vitro and in vivo validation and evaluation are warranted to establish how these drug compounds target the Nsp9 replicase and spike proteins.

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          Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China

          Summary Background A recent cluster of pneumonia cases in Wuhan, China, was caused by a novel betacoronavirus, the 2019 novel coronavirus (2019-nCoV). We report the epidemiological, clinical, laboratory, and radiological characteristics and treatment and clinical outcomes of these patients. Methods All patients with suspected 2019-nCoV were admitted to a designated hospital in Wuhan. We prospectively collected and analysed data on patients with laboratory-confirmed 2019-nCoV infection by real-time RT-PCR and next-generation sequencing. Data were obtained with standardised data collection forms shared by WHO and the International Severe Acute Respiratory and Emerging Infection Consortium from electronic medical records. Researchers also directly communicated with patients or their families to ascertain epidemiological and symptom data. Outcomes were also compared between patients who had been admitted to the intensive care unit (ICU) and those who had not. Findings By Jan 2, 2020, 41 admitted hospital patients had been identified as having laboratory-confirmed 2019-nCoV infection. Most of the infected patients were men (30 [73%] of 41); less than half had underlying diseases (13 [32%]), including diabetes (eight [20%]), hypertension (six [15%]), and cardiovascular disease (six [15%]). Median age was 49·0 years (IQR 41·0–58·0). 27 (66%) of 41 patients had been exposed to Huanan seafood market. One family cluster was found. Common symptoms at onset of illness were fever (40 [98%] of 41 patients), cough (31 [76%]), and myalgia or fatigue (18 [44%]); less common symptoms were sputum production (11 [28%] of 39), headache (three [8%] of 38), haemoptysis (two [5%] of 39), and diarrhoea (one [3%] of 38). Dyspnoea developed in 22 (55%) of 40 patients (median time from illness onset to dyspnoea 8·0 days [IQR 5·0–13·0]). 26 (63%) of 41 patients had lymphopenia. All 41 patients had pneumonia with abnormal findings on chest CT. Complications included acute respiratory distress syndrome (12 [29%]), RNAaemia (six [15%]), acute cardiac injury (five [12%]) and secondary infection (four [10%]). 13 (32%) patients were admitted to an ICU and six (15%) died. Compared with non-ICU patients, ICU patients had higher plasma levels of IL2, IL7, IL10, GSCF, IP10, MCP1, MIP1A, and TNFα. Interpretation The 2019-nCoV infection caused clusters of severe respiratory illness similar to severe acute respiratory syndrome coronavirus and was associated with ICU admission and high mortality. Major gaps in our knowledge of the origin, epidemiology, duration of human transmission, and clinical spectrum of disease need fulfilment by future studies. Funding Ministry of Science and Technology, Chinese Academy of Medical Sciences, National Natural Science Foundation of China, and Beijing Municipal Science and Technology Commission.
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            Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein

            Summary The emergence of SARS-CoV-2 has resulted in >90,000 infections and >3,000 deaths. Coronavirus spike (S) glycoproteins promote entry into cells and are the main target of antibodies. We show that SARS-CoV-2 S uses ACE2 to enter cells and that the receptor-binding domains of SARS-CoV-2 S and SARS-CoV S bind with similar affinities to human ACE2, correlating with the efficient spread of SARS-CoV-2 among humans. We found that the SARS-CoV-2 S glycoprotein harbors a furin cleavage site at the boundary between the S1/S2 subunits, which is processed during biogenesis and sets this virus apart from SARS-CoV and SARS-related CoVs. We determined cryo-EM structures of the SARS-CoV-2 S ectodomain trimer, providing a blueprint for the design of vaccines and inhibitors of viral entry. Finally, we demonstrate that SARS-CoV S murine polyclonal antibodies potently inhibited SARS-CoV-2 S mediated entry into cells, indicating that cross-neutralizing antibodies targeting conserved S epitopes can be elicited upon vaccination.
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              Structure, Function, and Evolution of Coronavirus Spike Proteins

              Fang Li (2016)
              The coronavirus spike protein is a multifunctional molecular machine that mediates coronavirus entry into host cells. It first binds to a receptor on the host cell surface through its S1 subunit and then fuses viral and host membranes through its S2 subunit. Two domains in S1 from different coronaviruses recognize a variety of host receptors, leading to viral attachment. The spike protein exists in two structurally distinct conformations, prefusion and postfusion. The transition from prefusion to postfusion conformation of the spike protein must be triggered, leading to membrane fusion. This article reviews current knowledge about the structures and functions of coronavirus spike proteins, illustrating how the two S1 domains recognize different receptors and how the spike proteins are regulated to undergo conformational transitions. I further discuss the evolution of these two critical functions of coronavirus spike proteins, receptor recognition and membrane fusion, in the context of the corresponding functions from other viruses and host cells.
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                Author and article information

                Journal
                J Biomol Struct Dyn
                J. Biomol. Struct. Dyn
                Journal of Biomolecular Structure & Dynamics
                Taylor & Francis
                0739-1102
                1538-0254
                24 August 2020
                2020
                : 1-14
                Affiliations
                [a ]Amity Institute of Molecular Medicine & Stem Cell Research (AIMMSCR), Amity University Uttar Pradesh , Noida, India
                [b ]Laboratory for Translational Chemistry and Drug Discovery, Department of Chemistry, Hansraj College, University of Delhi , Delhi, India
                [c ]Center of Emphasis in Cancer, Paul L. Foster School of Medicine, Department of Molecular and Translation Medicine, Texas Tech University Health Sciences Center , El Paso, TX, USA
                [d ]Shri B. M. Patil Medical College, Hospital and Research Centre, BLDE (Deemed to be University) , Vijayapura, India
                [e ]Laboratory of Computational Modelling of Drugs, South Ural State University , Chelyabinsk, Russia
                Author notes
                CONTACT Dhruv Kumar dhruvbhu@ 123456gmail.com ; dkumar13@ 123456amity.edu Amity Institute of Molecular Medicine & Stem Cell Research (AIMMSCR), Amity University Uttar Pradesh , Sec-125, Noida201313, India
                Article
                1811773
                10.1080/07391102.2020.1811773
                7484568
                32838660
                3bf401ff-7965-45ae-a046-dff6353fb803
                © 2020 Informa UK Limited, trading as Taylor & Francis Group

                This article is made available via the PMC Open Access Subset for unrestricted re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the COVID-19 pandemic or until permissions are revoked in writing. Upon expiration of these permissions, PMC is granted a perpetual license to make this article available via PMC and Europe PMC, consistent with existing copyright protections.

                History
                Page count
                Figures: 8, Tables: 4, Pages: 14, Words: 6882
                Categories
                Research Article
                Research Article

                sars-cov-2,nsp9 replicase,spike proteins,molecular docking,drug designing,drug repurposing

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