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      Identification of potential SARS-CoV-2 entry inhibitors by targeting the interface region between the spike RBD and human ACE2

      research-article
      a , * , b , c , d , d
      Journal of Infection and Public Health
      The Author(s). Published by Elsevier Ltd on behalf of King Saud Bin Abdulaziz University for Health Sciences.
      2019-nCoV, 2019 novel coronavirus, ACE2, Angiotensin-converting enzyme 2, Covid-19, Coronavirus disease 2019, DPP4, Dipeptidyl peptidase 4, LARMD, Ligand and Receptor Molecular Dynamics, MERS-CoV, Middle East respiratory syndrome coronavirus, MM-GBSA, Molecular mechanics-Generalized Born surface area, MM-PBSA, Molecular mechanics-Poisson–Boltzmann surface area, PCA, Principal component analysis, PDB, Protein Data Bank, PPIs, Protein-protein interactions, Q, Fraction of native contacts, RBD, Receptor-binding domain, Rg, Radius of gyration, RMSD, Root mean square deviation, ROF, Rule of five, SARS-CoV-2, Severe acute respiratory syndrome coronavirus-2, Receptor-binding domain, RBD, Angiotensin-converting enzyme 2, ACE2, Spike protein, Protein-protein interface, COVID-19, SARS-CoV-2, Molecular docking, Molecular dynamics simulation

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          Graphical abstract

          Highlights

          • The research highlights a novel strategy to block SARS-CoV-2 entry into the host cell.

          • High-throughput virtual screening identifies ZINC33039472 as a small molecule with favourable drug-like properties.

          • It shows higher binding affinity to the spike RBD interface region compared to emodin.

          • ZINC33039472 could be a potential drug candidate molecule for COVID-19.

          Abstract

          Coronavirus disease 2019 (COVID-19) is a fatal infectious disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). The virus infection is initiated upon recognition and binding of the spike (S) protein receptor-binding domain (RBD) to the host cell surface receptor, angiotensin-converting enzyme 2 (ACE2). Blocking the interaction between S protein and ACE2 receptor is a novel approach to prevent the viral entry into the host cell. The present study is aimed at the identification of small molecules which can disrupt the interaction between SARS-CoV-2 S protein and human ACE2 receptor by binding to the interface region. A chemical library consisting of 1,36,191 molecules were screened for drug-like compounds based on Lipinski’s rule of five, Verber’s rule and in silico toxicity parameters. The filtered drug-like molecules were next subjected to molecular docking in the interface region of RBD. The best three hits viz; ZINC64023823, ZINC33039472 and ZINC00991597 were further taken for molecular dynamics (MD) simulation studies and binding free energy evaluations using Molecular mechanics-Poisson–Boltzmann surface area (MM-PBSA) and Molecular mechanics-Generalized Born surface area (MM-GBSA). The protein-ligand complexes showed stable trajectories throughout the simulation time. ZINC33039472 exhibited binding free energy value lower as compared to the control (emodin) with a higher contribution by gas-phase energy and van der Waals energy to the total binding free energy. Thus, ZINC33039472 is identified to be a promising interfacial binding molecule which can inhibit the interaction between the viral S protein and human ACE2 receptor which would consequently help in the management of the disease.

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          Most cited references47

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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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            A pneumonia outbreak associated with a new coronavirus of probable bat origin

            Since the outbreak of severe acute respiratory syndrome (SARS) 18 years ago, a large number of SARS-related coronaviruses (SARSr-CoVs) have been discovered in their natural reservoir host, bats 1–4 . Previous studies have shown that some bat SARSr-CoVs have the potential to infect humans 5–7 . Here we report the identification and characterization of a new coronavirus (2019-nCoV), which caused an epidemic of acute respiratory syndrome in humans in Wuhan, China. The epidemic, which started on 12 December 2019, had caused 2,794 laboratory-confirmed infections including 80 deaths by 26 January 2020. Full-length genome sequences were obtained from five patients at an early stage of the outbreak. The sequences are almost identical and share 79.6% sequence identity to SARS-CoV. Furthermore, we show that 2019-nCoV is 96% identical at the whole-genome level to a bat coronavirus. Pairwise protein sequence analysis of seven conserved non-structural proteins domains show that this virus belongs to the species of SARSr-CoV. In addition, 2019-nCoV virus isolated from the bronchoalveolar lavage fluid of a critically ill patient could be neutralized by sera from several patients. Notably, we confirmed that 2019-nCoV uses the same cell entry receptor—angiotensin converting enzyme II (ACE2)—as SARS-CoV.
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              UCSF Chimera--a visualization system for exploratory research and analysis.

              The design, implementation, and capabilities of an extensible visualization system, UCSF Chimera, are discussed. Chimera is segmented into a core that provides basic services and visualization, and extensions that provide most higher level functionality. This architecture ensures that the extension mechanism satisfies the demands of outside developers who wish to incorporate new features. Two unusual extensions are presented: Multiscale, which adds the ability to visualize large-scale molecular assemblies such as viral coats, and Collaboratory, which allows researchers to share a Chimera session interactively despite being at separate locales. Other extensions include Multalign Viewer, for showing multiple sequence alignments and associated structures; ViewDock, for screening docked ligand orientations; Movie, for replaying molecular dynamics trajectories; and Volume Viewer, for display and analysis of volumetric data. A discussion of the usage of Chimera in real-world situations is given, along with anticipated future directions. Chimera includes full user documentation, is free to academic and nonprofit users, and is available for Microsoft Windows, Linux, Apple Mac OS X, SGI IRIX, and HP Tru64 Unix from http://www.cgl.ucsf.edu/chimera/. Copyright 2004 Wiley Periodicals, Inc.
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                Author and article information

                Journal
                J Infect Public Health
                J Infect Public Health
                Journal of Infection and Public Health
                The Author(s). Published by Elsevier Ltd on behalf of King Saud Bin Abdulaziz University for Health Sciences.
                1876-0341
                1876-035X
                21 December 2020
                21 December 2020
                Affiliations
                [a ]Department of Basic Sciences and Social Sciences, North-Eastern Hill University, Shillong 793022, Meghalaya, India
                [b ]Department of Botany and Microbiology, College of Science, King Saud University, Riyadh, 11451, Saudi Arabia
                [c ]Department of Environment and Forest Resources, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon 34134, Republic of Korea
                [d ]Department of Zoology, College of Science, King Saud University, Riyadh, 11451, Saudi Arabia
                Author notes
                [* ]Corresponding author.
                Article
                S1876-0341(20)30770-X
                10.1016/j.jiph.2020.12.014
                7752028
                33493919
                8ba774a1-a7d1-4189-a0cd-28523d83a40a
                © 2020 The Author(s). Published by Elsevier Ltd on behalf of King Saud Bin Abdulaziz University for Health Sciences.

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

                History
                : 16 September 2020
                : 4 November 2020
                : 8 December 2020
                Categories
                Article

                2019-ncov, 2019 novel coronavirus,ace2, angiotensin-converting enzyme 2,covid-19, coronavirus disease 2019,dpp4, dipeptidyl peptidase 4,larmd, ligand and receptor molecular dynamics,mers-cov, middle east respiratory syndrome coronavirus,mm-gbsa, molecular mechanics-generalized born surface area,mm-pbsa, molecular mechanics-poisson–boltzmann surface area,pca, principal component analysis,pdb, protein data bank,ppis, protein-protein interactions,q, fraction of native contacts,rbd, receptor-binding domain,rg, radius of gyration,rmsd, root mean square deviation,rof, rule of five,sars-cov-2, severe acute respiratory syndrome coronavirus-2,receptor-binding domain,rbd,angiotensin-converting enzyme 2,ace2,spike protein,protein-protein interface,covid-19,sars-cov-2,molecular docking,molecular dynamics simulation

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