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    SARS-CoV-2 spike PROTEIN protein predicted to form stable complexes with host receptor protein orthologues from mammals, but not fish, birds or reptiles

    Authors: Su Datt Lam; Nicola Bordin; Vaishali P Waman; Harry M Scholes; Paul Ashford; Neeladri Sen; Lucy van Dorp; Clemens Rauer; Natalie L Dawson; Camilla SM Pang; Mahnaz Abbasian; Ian Sillitoe; Sarah JL Edwards; Jonathan G Lees; Joanne M Santini; Christine A Orengo

    doi:10.1101/2020.05.01.072371 Date: 2020-05-01 Source: bioRxiv

    SARS-CoV-2 has a zoonotic origin and was transmitted to humans via an undetermined intermediate host, leading to infections in humans and other mammals. To enter host cells, the viral spike protein (S PROTEIN S-protein HGNC) binds to its receptor, ACE2 HGNC, and is then processed by TMPRSS2 HGNC. Whilst receptor binding contributes to the viral host range, S-protein PROTEIN S-protein HGNC: ACE2 HGNC complexes from other animals have not been investigated widely. To predict infection risks, we modelled S-protein HGNC S-protein PROTEIN: ACE2 HGNC complexes from 215 vertebrate species, calculated changes in the energy of the complex caused by mutations in each species, relative to human ACE2 HGNC, and correlated these changes with COVID-19 MESHD infection data. We also analysed structural interactions to better understand the key residues contributing to affinity. We predict that mutations are more detrimental in ACE2 HGNC than TMPRSS2 HGNC. Finally, we demonstrate phylogenetically that human SARS-CoV-2 strains have been isolated in animals. Our results suggest that SARS-CoV-2 can infect a broad range of mammals, but few fish, birds or reptiles. Susceptible animals could serve as reservoirs of the virus, necessitating careful ongoing animal management and surveillance.

    Identification of a Potent Inhibitor Targeting the Spike Protein PROTEIN of Pandemic Human Coronavirus, SARS-CoV-2 by Computational Methods

    Authors: SRUTHI UNNI; Snehal Aouti; Padmanabhan Balasundaram

    doi:10.26434/chemrxiv.12197934.v1 Date: 2020-04-27 Source: ChemRxiv

    Severe acute respiratory syndrome coronavirus (SARS-CoV-2 MESHD) is an emerging new viral pathogen that causes severe respiratory disease MESHD. SARS-CoV-2 is responsible for an outbreak of COVID-19 pandemic MESHD COVID-19 pandemic MESHD worldwide. As there are no confirmed antiviral drugs or vaccines currently available for the treatment of COVID-19 MESHD, discovering potent inhibitors or vaccines are urgently required for the benefit of humanity. The glycosylated Spike protein (S PROTEIN S-protein HGNC) directly interacts with human angiotensin-converting enzyme 2 HGNC ( ACE2 HGNC) receptor through the receptor-binding domain (RBD) of S-protein HGNC S-protein PROTEIN. As the S-protein HGNC S-protein PROTEIN is exposed to the surface and is essential for entry into the host, the S-protein HGNC S-protein PROTEIN can be considered as a first-line therapeutic target for antiviral therapy and vaccine development. In-silico screening, docking and molecular dynamics simulation studies were performed to identify repurposing drugs using DrugBank and PubChem library against the RBD of S-protein PROTEIN S-protein HGNC. The study identified a laxative drug, Bisoxatin (DB09219), which is used for the treatment of constipation MESHD and preparation of the colon for surgical procedures. It binds nicely at the S-protein PROTEIN S-protein HGNC ACE2 HGNC interface by making substantial pi-pi interactions with Tyr505 in the ‘Site 1’ hook region of RBD and hydrophilic interactions with Glu406, Ser494 and Thr500. Bisoxatin consistently binds to the protein throughout the 100 ns simulation. Taken together, we propose that the discovered molecule, Bisoxatin may be a potent repurpose drug to develop new chemical libraries for inhibiting SARS-CoV-2 entry into the host.

    ACE2 HGNC Homo-dimerization, Human Genomic variants and Interaction of Host Proteins Explain High Population Specific Differences in Outcomes of COVID19 MESHD

    Authors: Swarkar Sharma; Inderpal Singh; Shazia Haider; Md. Zubbair Malik; Kalaiarasan Ponnusamy; Ekta Rai

    doi:10.1101/2020.04.24.050534 Date: 2020-04-24 Source: bioRxiv

    Severe acute respiratory syndrome coronavirus 2 MESHD (SARS-CoV-2) is a positive single-stranded RNA virus that causes a highly contagious Corona Virus Disease MESHD ( COVID19 MESHD). Entry of SARS-CoV-2 in human cells depends on binding of the viral spike (S) proteins PROTEIN to cellular receptor Angiotensin-converting enzyme 2 ( ACE2 HGNC) and on S-protein PROTEIN S-protein HGNC priming by host cell serine protease TMPRSS2 HGNC. Recently, COVID19 MESHD has been declared pandemic by World Health Organization (WHO) yet high differences in disease outcomes across countries have been seen. We provide evidences to explain these population-level differences. One of the key factors of entry of the virus in host cells presumably is because of differential interaction of viral proteins with host cell proteins due to different genetic backgrounds. Based on our findings, we conclude that a higher expression of ACE2 HGNC is facilitated by natural variations, acting as Expression quantitative trait loci (eQTLs), with different frequencies in different populations. We suggest that high expression of ACE2 HGNC results in homo-dimerization, proving disadvantageous for TMPRSS2 HGNC mediated cleavage of ACE2 HGNC; whereas, the monomeric ACE2 HGNC has higher preferential binding with SARS-CoV-2 S-Protein vis MESHD S-Protein PROTEIN S-Protein HGNC vis-a-vis its dimerized counterpart. Further, eQTLs in TMPRSS2 HGNC and natural structural variations in the gene may also result in differential outcomes towards priming of viral S-protein HGNC S-protein PROTEIN, a critical step for entry of the Virus in host cells. In addition, we suggest that several key host genes, like SLC6A19 HGNC, ADAM17 HGNC, RPS6 HGNC, HNRNPA1 HGNC, SUMO1 HGNC, NACA HGNC, BTF3 HGNC and some other proteases as Cathepsins, might have a critical role. To conclude, understanding population specific differences in these genes may help in developing appropriate management strategies for COVID19 MESHD with better therapeutic interventions.

    Antibodies to SARS-CoV-2 and Their Potential for Therapeutic Passive Immunization

    Authors: P.J. Klasse; John P. Moore

    id:10.20944/preprints202004.0326.v1 Date: 2020-04-19 Source: Preprints.org

    We review aspects of the antibody response to SARS-CoV-2, the causative agent of the COVID- 19 pandemic. The topics we cover are relevant to immunotherapy with plasma from recovered patients and with monoclonal antibodies against the viral S-protein PROTEIN S-protein HGNC. The development of vaccines against SARS-CoV-2, an essential public health tool, will also be informed by an understanding of the antibody response in infected patients. Although virus-neutralizing antibodies are likely to protect, antibodies could potentially trigger immunopathogenic events in SARS-CoV-2-infected patients or enhance infection. An awareness of these possibilities may benefit clinicians and the developers of antibody-based therapies and vaccines.

    Identification of SARS-CoV-2 Cell Entry Inhibitors by Drug Repurposing Using in Silico Structure-Based Virtual Screening Approach

    Authors: Shweta Choudhary; Yashpal S. Malik; Shailly Tomar

    doi:10.26434/chemrxiv.12005988.v2 Date: 2020-04-15 Source: ChemRxiv

    The rapidly spreading, highly contagious and pathogenic SARS-coronavirus MESHD 2 (SARS-CoV-2) associated Coronavirus Disease 2019 MESHD ( COVID-19 MESHD) has been declared as a pandemic by the World Health Organization (WHO). The novel 2019 SARS-CoV-2 enters the host cell by binding of the viral surface spike glycoprotein PROTEIN ( S-protein HGNC S-protein PROTEIN) to angiotensin converting enzyme 2 HGNC ( ACE2 HGNC). The virus specific molecular interaction with the host cell represents a promising therapeutic target for identifying SARS-CoV-2 antiviral drugs. The repurposing of drugs can provide a rapid and potential cure towards exponentially expending COVID-19 MESHD. Thereto, high-throughput virtual screening approach was used to investigate FDA approved LOPAC library drugs against both the S-protein HGNC S-protein PROTEIN and ACE2 HGNC host cell receptor. Primary screening identified a few promising drugs for both the targets, which were further analyzed in details by their binding energy, binding modes through molecular docking, dynamics and simulations. Evidently, Eptifibatide acetate, TNP, GNF5, GR 127935 hydrochloride hydrate and RS504393 were found binding to virus binding motifs of ACE2 HGNC receptor. Additionally, KT185, KT203 GSK1838705A, BMS195614, and RS504393 were identified to bind at the receptor binding site on the viral S-protein HGNC S-protein PROTEIN. These identified drug molecules may effectively assist in controlling the rapid spread of SARS-COV-2 by not only potentially inhibiting the virus at entry step but also as anti-inflammatory agents which could impart relief in lung injuries MESHD. Timely identification and determination of an effective drug to combat and tranquilize the COVID-19 MESHD global crisis is the utmost need of hour. Further, prompt in vivo testing to validate the anti-SARS-COV-2 inhibition by these drugs could save lives is justified.

    Human ACE2 HGNC receptor polymorphisms predict SARS-CoV-2 susceptibility

    Authors: Eric W Stawiski; Devan Diwanji; Kushal Suryamohan; Ravi Gupta; Frederic A Fellouse; Fah Sathirapongsasuti; Jiang Liu; Ying-Ping Jiang; Aakrosh Ratan; Monika Mis; Devi Santhosh; Sneha Somasekar; Sangeetha Mohan; Sameer Phalke; Boney Kuriakose; Aju Antony; Jagath R Junutula; Stephan C Schuster; Natalia Jura; Somasekar Seshagiri

    doi:10.1101/2020.04.07.024752 Date: 2020-04-10 Source: bioRxiv

    Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of coronavirus disease MESHD ( COVID-19 MESHD) that has resulted in a global pandemic. It is a highly contagious positive strand RNA virus and its clinical presentation includes severe to critical respiratory disease MESHD that appears to be fatal in [~]3-5% of the cases. The viral spike (S) coat protein engages the human angiotensin-converting enzyme2 HGNC ( ACE2 HGNC) cell surface protein to invade the host cell. The SARS-CoV-2 S-protein PROTEIN S-protein HGNC has acquired mutations that increase its affinity to human ACE2 HGNC by [~]10-15-fold compared to SARS-CoV S-protein MESHD S-protein PROTEIN S-protein HGNC, making it highly infectious. In this study, we assessed if ACE2 HGNC polymorphisms might alter host susceptibility to SARS-CoV-2 by affecting the ACE2 S-protein PROTEIN interaction. Our comprehensive analysis of several large genomic datasets that included over 290,000 samples representing >400 population groups identified multiple ACE2 HGNC protein-altering variants, some of which mapped to the S-protein PROTEIN S-protein HGNC-interacting ACE2 HGNC surface. Using recently reported structural data and a recent S-protein HGNC S-protein PROTEIN-interacting synthetic mutant map of ACE2 HGNC, we have identified natural ACE2 HGNC variants that are predicted to alter the virus-host interaction and thereby potentially alter host susceptibility. In particular, human ACE2 HGNC variants S19P, I21V, E23K, K26R, T27A, N64K, T92I, Q102P and H378R are predicted to increase susceptibility. The T92I variant, part of a consensus NxS/T N-glycosylation motif, confirmed the role of N90 glycosylation in immunity from non-human CoVs. Other ACE2 HGNC variants K31R, N33I, H34R, E35K, E37K, D38V, Y50F, N51S, M62V, K68E, F72V, Y83H, G326E, G352V, D355N, Q388L and D509Y are putative protective variants predicted to show decreased binding to SARS-CoV-2 S-protein PROTEIN S-protein HGNC. Overall, ACE2 HGNC variants are rare, consistent with the lack of selection pressure given the recent history of SARS-CoV MESHD epidemics, however, are likely to play an important role in altering susceptibility to CoVs.

    ACE2 HGNC fragment as a decoy for novel SARS-Cov-2 virus

    Authors: Fabiana Renzi; Dario Ghersi

    doi:10.1101/2020.04.06.028647 Date: 2020-04-10 Source: bioRxiv

    Novel SARS-Cov-2 enters human cells via interaction between the surface spike ( S) glycoprotein PROTEIN and the cellular membrane receptor angiotensin-converting enzyme 2 ( ACE2 HGNC). Using a combination of comparative structural analyses of the binding surface of the S protein PROTEIN S protein HGNC to ACE2 HGNC, docking experiments, and molecular dynamics simulations we computationally identified a minimal, stable fragment of ACE2 HGNC. This fragment binds to the S protein HGNC S protein PROTEIN, is soluble, and appears not to bind to the physiological ligand angiotensinII. These results suggest a possible use of the ACE2 HGNC fragment as a decoy that could interfere with viral binding by competition.

    Catechin and Curcumin interact with corona (2019-nCoV/SARS-CoV2) viral S protein PROTEIN and ACE2 HGNC of human cell membrane: insights from Computational study and implication for intervention

    Authors: Atala B. Jena; Namrata Kanungo; Vinayak Nayak; G.B.N. Chainy; Jagneshwar Dandapat

    doi:10.21203/rs.3.rs-22057/v1 Date: 2020-04-08 Source: ResearchSquare

    The recent outbreak of the coronavirus (2019n-CoV) is an unprecedented threat for human health throughout the globe. In this regards development of a suitable intervention is the need of the hour. The viral spike protein (S PROTEIN S-Protein HGNC) and the cognate host cell receptor ACE2 HGNC can prove to be effective. Here, through computational approaches we have reported two polyphenols, Catechin and Curcumin which have dual binding affinity i.e both the molecule binds to viral S-protein HGNC S-protein PROTEIN and as well as ACE2 HGNC. Catechin binds with S-protein PROTEIN S-protein HGNC and ACE2 HGNC with binding energy of -10.5 Kcal/mol and -8.9 Kcal/mol, respectively. Catechin binds with a greater affinty than that of curcumin which has a binding energy of -7.9Kcal/mol and - 7.8Kcal/mol for S-protein HGNC S-protein PROTEIN and ACE2 HGNC, respectively. While curcumin gets bound directly to receptor binding domain (RBD) of viral S-protein HGNC S-protein PROTEIN, catechin binds to near proximity of RBD sequence of S-protein HGNC S-protein PROTEIN. Molecular simulation study demonstrates that curcumin directly binds with RBD site of S-protein HGNC S-protein PROTEIN during 40-100ns. In contrast, catechin binds with S-protein PROTEIN S-protein HGNC near the RBD site and causes fluctuation in the amino acids present in the RBD and it’s near proximity. In conclusion, this computational study for the first time predicts the possibility of above two polyphenols, for therapeutic/preventive intervention.

    Evaluation of Flavonoids as 2019-nCoV Cell Entry Inhibitor Through Molecular Docking and Pharmacological Analysis

    Authors: Deep Bhowmik; Rajat Nandi; Diwakar Kumar

    doi:10.26434/chemrxiv.12071508.v1 Date: 2020-04-06 Source: ChemRxiv

    In this study we aimed at the receipt binding domain of S protein HGNC S protein PROTEIN and ACE-2 HGNC receptor as a promising drug targets against SARS-CoV-2. Flavonoids with anti-viral properties were taken as ligand for molecular docking. Selected flavonoids showed extremely good pharmacokinetics properties with good absorption, solubility, metabolism, excretion,distribution, bioavailability and minimal toxicity MESHD. These identified lead flavonoids may act as potential compound for the development of effective drugs and may help in controlling the rapid spread of SARS-CoV-2 by potentially inhibiting the virus entry into the host cell.

    In Silico Screening of Some Naturally Occurring Bioactive Compounds Predicts Potential Inhibitors against SARS-COV-2 ( COVID-19 MESHD) Protease

    Authors: Ashok Kumar Mishra; Satya Prakash Tewari

    id:2004.01634v1 Date: 2020-04-03 Source: arXiv

    SARS-COV-2 identified as COVID-19 MESHD in Wuhan city of China in the month of December, 2019 has now been declared as pandemic by World Health Organization whose transmission chain and cure both have emerged as a tough problem for the medical fraternity. The reports pertaining to the treatment of this pandemic are still lacking. We firmly believe that Nature itself provides a simple solution for any complicated problem created in it which motivated us to carry out In Silico investigations on some bioactive natural compounds reportedly found in the fruits and leaves of Anthocephalus Cadamba which is a miraculous plant found on the earth aiming to predict the potential inhibitors against aforesaid virus. Having modeled the ground state ligand structure of the such nine natural compounds applying density functional theory at B3LYP/631+G (d, p) level we have performed their molecular docking with SARS-COV-2 protease to calculate the binding affinity as well as to screen the binding at S-protein HGNC S-protein PROTEIN site during ligand-protein interactions. Out of these nine studied naturally occurring compounds; Oleanic Acid has been appeared to be potential inhibitor for COVID-19 MESHD followed by Ursolic Acid, IsoVallesiachotamine,Vallesiachotamine,Cadambine,Vincosamide-N-Oxide, Isodihydroamino-cadambine, Pentyle Ester of Chlorogenic Acid and D-Myo-Inositol. Hence these bioactive natural compounds or their structural analogs may be explored as anti- COVID19 MESHD drug agent which will be possessing the peculiar feature of cost-less synthesis and less or no side effect due to their natural occurrence. The solubility and solvent-effect related to the phytochemicals may be the point of concern. The In-vivo investigations on these proposed natural compounds or on their structural analogs are invited for designing and developing the potential medicine/vaccine for the treatment of COVID-19 pandemic MESHD.

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins


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