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    Sequence Conservation Analysis and Screening of Ayurvedic compounds against SARS-CoV-2 Spike PROTEIN protein

    Authors: Zarrin Basharat; Muhammad Jahanzaib; Noor Rahman; Ishtiaq Ahmad Khan; Azra Yasmin

    doi:10.21203/rs.3.rs-63923/v2 Date: 2020-08-22 Source: ResearchSquare

    Recent infections caused by the novel coronavirus (SARS-CoV-2) have led to global panic and mortality. Here, we analyzed the spike (S) protein PROTEIN of this virus using bioinformatics tools. We aimed to determine relative changes among different coronavirus species over the past two decades and to understand the conservation of the S-protein PROTEIN S-protein HGNC. Representative sequences of coronaviruses were collected from humans and other animals between 2000 and 2020. Evolutionary analyses found that the S-protein HGNC S-protein PROTEIN did not evolve overnight, but rather continuously over time. Virtual screening of S-protein PROTEIN S-protein HGNC against a phytochemical database of Ayurvedic medicinal compounds (n = 2103) identified the S-protein HGNC S-protein PROTEIN inhibitors. Among these, top ranked were Gingerol (IUPAC name: 4'-Me ether, 3,5-di-Ac 3,5-di-Gingerdiols), 1-(5-Butyltetrahydro-2-furanyl)-2-hexacosanone and Ginsenoyne N ginseng that stimulates Caspase-3, Caspase-8, and the immune system. Gingerol is found in the fresh ginger and has reputation of being a potent antiviral. These compounds might prove useful to design drugs against COVID-19 MESHD.

    Spike Protein PROTEIN of SARS-CoV-2: Impact of Single Amino Acid Mutation and Effect of Drug Binding to the Variant-in Silico Analysis

    Authors: Pratibha Manickavasagam

    id:10.20944/preprints202008.0447.v1 Date: 2020-08-20 Source: Preprints.org

    Novel SARS-CoV-2, a bat based virus originated in Wuhan, China that caused a global pandemic in December, 2019 belongs to the Betacorona virus family and contains single stranded genome of ~29Kbp. The host cell invasion of SARS-CoV-2 is facilitated by interaction of C-Terminal Domain (CTD) of Spike (S) protein PROTEIN of virus and host ACE2 HGNC receptor in the presence of TMPRSS seine protease secreted by the host cell. In this study the mutation hotspots of S-protein HGNC S-protein PROTEIN will be identified and the impact of such mutation in the binding affinity will be studied. Additionally, the lead molecule which can bind to the mutated protein also will be identified. Multiple sequence alignment of the spike protein PROTEIN sequence of SARS-CoV-2 shows the number of single amino acid mutation hotspots such as L5F, R214L, R408I, G476S, V483A, H519Q, A520S, T572I, D614G and H655Y. Among these mutations D614G has 57.5% occurrence and G476S, V483A has 7.5% occurrence. The mutated proteins were modelled based on wild type homolog and docked to ACE2 HGNC receptor. When the mutated S protein PROTEIN is docked, the ∆G (binding free energy) value is very minimal in mutated protein showed the stability of variants. By the drug repurposing method, 1000 FDA approved drugs were virtually screened for its binding to RBD of S1 domain. Among these drugs Digitoxin, Gliquidone and Zorubicin Hcl binds to spike proteins PROTEIN with higher docking score (lesser than -8.5 Kcal/mol) to both wild type and mutants.

    Quantifying the adhesive strength between the SARS-CoV-2 S-proteins PROTEIN and human receptor and its effect in therapeutics

    Authors: Mauricio Ponga de la Torre

    doi:10.21203/rs.3.rs-57159/v2 Date: 2020-08-11 Source: ResearchSquare

    The binding affinity and adhesive strength between the spike ( S) glycoproteins PROTEIN of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the human angiotensin-converting enzyme 2 HGNC ( ACE2 HGNC) receptor is computed using molecular dynamics (MD) simulations. The calculations indicate that the binding affinity is eRS= 12.6 +/- 1 kCal mol-1 with a maximum adhesive force of ~102 pN. Our analysis suggests that only 27 (13 in S-protein HGNC S-protein PROTEIN, 14 in ACE2 HGNC) residues are active during the initial fusion process between the S-protein PROTEIN S-protein HGNC and ACE2 HGNC receptor. With these insights, we investigated the effect of possible therapeutics in the size and wrapping time of virus particles by reducing the binding energy. Our analysis indicates that this energy has to be reduced significantly, around 50\% or more, to block SARS-CoV-2 particles with radius in the order of R < 60 nm. Our study provides concise target residues and target binding energy reduction between S-proteins PROTEIN and receptors for the development of new therapeutics treatments for COVID-19 MESHD guided by computational design.

    Neutralizing antibody response in non-hospitalized SARS-CoV-2 patients

    Authors: Natalia Ruetalo; Ramona Businger; Karina Althaus; Simon Fink; Felix Ruoff; Klaus Hamprecht; Bertram Flehmig; Tamam Bakchoul; Markus F Templin; Michael Schindler

    doi:10.1101/2020.08.07.20169961 Date: 2020-08-07 Source: medRxiv

    The majority of infections with SARS-CoV-2 ( SCoV2 MESHD) are asymptomatic or mild without the necessity of hospitalization. It is of outmost importance to reveal if these patients develop an antibody response against SCoV2 MESHD and to define which antibodies confer virus neutralization. We hence conducted a comprehensive serological survey of 49 patients with a mild course of disease and quantified neutralizing antibody responses against authentic SCoV2 MESHD employing human cells as targets. Four patients (8%), even though symptomatic, did not develop antibodies against SCoV2 MESHD and two other sera (4%) were only positive in one of the serological assays employed. For the remainder, antibody response against the S-protein PROTEIN S-protein HGNC correlated with serum neutralization whereas antibodies against the nucleocapsid were poor predictors of virus neutralization. Only six sera (12%) could be classified as highly neutralizing. Furthermore, sera from several individuals with fairly high antibody levels had only poor neutralizing activity. In addition, our data suggest that antibodies against the seasonal coronavirus 229E contribute to SCoV2 MESHD neutralization. Altogether, we show that there is a wide breadth of antibody responses against SCoV2 MESHD in patients that differentially correlate with virus neutralization. This highlights the difficulty to define reliable surrogate markers for immunity against SCoV2 MESHD.

    DNA Aptamers Block the Receptor Binding Domain at the Spike Protein PROTEIN of SARS-CoV-2

    Authors: Fabrizio Cleri; Marc F. Lensink; Ralf Blossey

    doi:10.26434/chemrxiv.12696173.v1 Date: 2020-07-24 Source: ChemRxiv

    DNA aptamers are versatile molecular species obtained by the folding of short single-stranded nucleotide sequences, with highly specific recognition capabilities against proteins. Here we test the ability of selected DNA aptamers in interacting with the spike (S-)protein PROTEIN of the SARS-CoV-2 viral capsid. The S-protein PROTEIN S-protein HGNC, a trimer made up of several subdomains, develops the crucial function of recognizing the ACE2 HGNC receptors on the surface of human cells, and sub- sequent fusioning of the virus membrane with the host cell membrane. In order to do this, the S1 domain of one protomer switches between a closed conformation, in which the binding site is inaccessible to the cell receptors, and an open conformation, in which ACE2 HGNC can bind, thereby initiating the entry process of the viral genetic material in the host cell. Here we show by means of state-of-the-art molecular simulations that small DNA aptamers can recognize the S-protein PROTEIN S-protein HGNC of SARS-CoV-2. Moreover, their interaction with different regions of the S-protein HGNC S-protein PROTEIN can effectively block, or at least considerably slow down the opening process of the S1 domain, thereby largely reducing the probability of virus-cell binding. We also provide evidence that binding of the human ACE2 receptor may be drastically affected under such conditions. Given the facility and low cost of fabrication of specific aptamers, the present findings could open the way to both an innovative viral screening technique with sub-nanomolar sensitivity, and to an effective and low impact curative strategy.

    Chemical composition and pharmacological mechanism of Ephedra-Glycyrrhiza drug pair  against coronavirus disease 2019 MESHD ( COVID-19 MESHD)

    Authors: Qin Qiu; Mingyue Li; Haowen Lin; Shilin Cao; Qu Wang; Xiaoling Li; Zishi Chen; Wenhao Jiang; Yuge Huang; Hui Luo; lianxiang luo

    doi:10.21203/rs.3.rs-46829/v1 Date: 2020-07-21 Source: ResearchSquare

    Background:  Coronavirus disease 2019 MESHD ( COVID-19 MESHD) is currently spreading all over the world, and the prospect of a very rapid increase in COVID-19 MESHD cases prompted us to seek effective antiviral therapeutics, from the identification of possible drugs to their potential mechanisms. Purpose: The aim of this study was to explore the efficacy of the Ephedra-Glycyrrhiza (EG) drug pair on coronavirus disease 2019 MESHD ( COVID-19 MESHD) by network pharmacology and molecular docking. Methods: The main active compounds, target information, meridians and properties of EG were obtained through the TCMSP and ETCM databases. The targeted information of COVID-19 MESHD was acquired from the GeneCards database. EG drug pair applied diseases were analysed by DAVID and the drug-bank database, and visualized by Rstudio and Cytoscape 3.7.2. Then, we carried out targeted intersection of the EG drug pair and COVID-19 MESHD to map the compound-target-disease interactions and visualize them with Cytoscape 3.7.2 and Venny 2.1. In addition, the enrichment analysis of the GO and KEGG pathways were visualized with Rstudio and PathVisio software through the DAVID database. Finally, we carried out the molecular docking of the EG active compounds with M hydrolase ( Mpro PROTEIN), spike protein (S PROTEIN S protein HGNC) and angiotensin-converting enzyme 2 HGNC ( ACE2 HGNC), and the binding modes between GE and the protein were verified via molecular dynamics (MD) simulation. Results: We identified 112 active EG compounds by network pharmacological analysis. Drug pair enrichment analysis demonstrated that these compounds may participate in the cAMP, PI3K-Akt, JAK-STAT and chemokine signalling pathways, which had a high correlation with respiratory system, nervous system, blood circulation system and digestive system related diseases. Pathway analysis between EG and COVID-19 MESHD showed that the key targets were TNF HGNC, IL2 HGNC, FOS HGNC, ALB HGNC and PTGS2 HGNC. They may regulate the PI3K-Akt signalling pathway and natural killer cell-mediated cytotoxicity MESHD to play roles in immune regulation, organ protection, antiviral, immune regulation, and organ protection as well as having antiviral effects. Molecular docking results showed that the active EG compounds bind well to Mpro PROTEIN, S protein HGNC S protein PROTEIN and ACE2 HGNC. The binding modes between the active compounds of the EG and protein were verified via MD simulation. Conclusion: The EG drug pair can treat COVID-19 MESHD through multiple targets and pathways, which can provide a theoretical basis for further study of the mechanism of action of the EG drug pair on COVID-19 MESHD.

    Humoral Response Dynamics Following Infection with SARS-CoV-2

    Authors: Louis Grandjean; Anja Saso; Arturo Ortiz; Tanya Lam; James Hatcher; Rosie Thistlethwaite; Mark Harris; Timothy Best; Marina Johnson; Helen Wagstaffe; Elizabeth Ralph; Annabelle Mai; Caroline Colijn; Judith Breuer; Matthew Buckland; Kimberly Gilmour; David Goldblatt; - The Co-Stars Study Team

    doi:10.1101/2020.07.16.20155663 Date: 2020-07-21 Source: medRxiv

    Introduction: Severe Acute Respiratory Syndrome Coronavirus-2 MESHD (SARS-CoV-2) specific antibodies have been shown to neutralize the virus in-vitro. Understanding antibody dynamics following SARS-CoV-2 infection MESHD is therefore crucial. Sensitive measurement of SARS-CoV-2 antibodies is also vital for large seroprevalence surveys which inform government policies and public health interventions. However, rapidly waning antibodies following SARS-CoV-2 infection MESHD could jeopardize the sensitivity of serological testing on which these surveys depend. Methods: This prospective cohort study of SARS-CoV-2 humoral dynamics in a central London hospital analyzed 137 serial samples collected from 67 participants seropositive to SARS-CoV-2 by the Meso-Scale Discovery assay. Antibody titers were quantified to the SARS-CoV-2 nucleoprotein (N PROTEIN), spike (S-)protein PROTEIN S-)protein HGNC and the receptor-binding-domain (RBD) of the S-protein HGNC S-protein PROTEIN. Titers were log-transformed and a multivariate log-linear model with time-since-infection and clinical variables was fitted by Bayesian methods. Results: The mean estimated half-life of the N-antibody was 52 days (95% CI 42-65). The S- and RBD-antibody had significantly longer mean half-lives of 81 days (95% CI 61-111) and 83 days (95% CI 55-137) respectively. An ACE-2-receptor competition assay demonstrated significant correlation between the S and RBD-antibody titers and ACE2-receptor blocking in-vitro. The time-to-a-negative N-antibody test for 50% of the seropositive population was predicted to be 195 days (95% CI 163-236). Discussion: After SARS-CoV-2 infection MESHD, the predicted half-life of N-antibody was 52 days with 50% of seropositive participants becoming seronegative to this antibody at 195 days. Widely used serological tests that depend on the N-antibody will therefore significantly underestimate the prevalence of infection following the majority of infections.

    Artificial Intelligence Guided De Novo Molecular Design Targeting COVID-19 MESHD

    Authors: Srilok Srinivasan; Rohit Batra; Henry Chan; Ganesh Kamath; Mathew J. Cherukara; Subramanian Sankaranarayanan

    doi:10.26434/chemrxiv.12581075.v1 Date: 2020-06-30 Source: ChemRxiv

    An extensive search for active therapeutic agents against the SARS-CoV-2 is being conducted across the globe. Computational docking simulations have traditionally been used for in silico ligand design and remain popular method of choice for high-throughput screening of therapeutic agents in the fight against COVID-19 MESHD. Despite the vast chemical space (millions to billions of biomolecules) that can be potentially explored as therapeutic agents, we remain severely limited in the search of candidate compounds owing to the high computational cost of these ensemble docking simulations employed in traditional in silico ligand design. Here, we present a de novo molecular design strategy that leverages artificial intelligence to discover new therapeutic biomolecules against SARS-CoV-2. A Monte Carlo Tree Search algorithm combined with a multi-task neural network (MTNN) surrogate model for expensive docking simulations and recurrent neural networks (RNN) for rollouts, is used to sample the exhaustive SMILES space of candidate biomolecules. Using Vina scores as target objective to measure binding of therapeutic molecules to either the isolated spike protein (S PROTEIN S-protein HGNC) of SARS-CoV-2 at its host receptor region or to the S-protein PROTEIN S-protein HGNC: Angiotensin converting enzyme 2 HGNC ( ACE2 HGNC) receptor interface, we generate several (~100's) new biomolecules that outperform FDA (~1000’s) and non-FDA biomolecules (~million) from existing databases. A transfer learning strategy is deployed to retrain the MTNN surrogate as new candidate molecules are identified - this iterative search and retrain strategy is shown to accelerate the discovery of desired candidates. We perform detailed analysis using Lipinski's rules and also analyze the structural similarities between the various top performing candidates. We spilt the molecules using a molecular fragmenting algorithm and identify the common chemical fragments and patterns – such information is important to identify moieties that are responsible for improved performance. Although we focus on therapeutic biomolecules, our AI strategy is broadly applicable for accelerated design and discovery of any chemical molecules with user-desired functionality.

    Glycans on the SARS-CoV-2 Spike PROTEIN Control the Receptor Binding Domain Conformation

    Authors: Rory Henderson; Robert J Edwards; Katayoun Mansouri; Katarzyna Janowska; Victoria Stalls; Megan Kopp; Barton F Haynes; Priyamvada Acharya

    doi:10.1101/2020.06.26.173765 Date: 2020-06-26 Source: bioRxiv

    The glycan shield of the beta-coronavirus (β-CoV) Spike ( S) glycoprotein PROTEIN provides protection from host immune responses, acting as a steric block to potentially neutralizing antibody responses. The conformationally dynamic S-protein HGNC S-protein PROTEIN is the primary immunogenic target of vaccine design owing to its role in host-cell fusion, displaying multiple receptor binding domain (RBD) ‘up’ and ‘down’ state configurations. Here, we investigated the potential for RBD adjacent, N-terminal domain (NTD) glycans to influence the conformational equilibrium of these RBD states. Using a combination of antigenic screens and high-resolution cryo-EM structure determination, we show that an N-glycan deletion at position 234 results in a dramatically reduced population of the ‘up’ state RBD position. Conversely, glycan deletion at position N165 results in a discernable increase in ‘up’ state RBDs. This indicates the glycan shield acts not only as a passive hinderance to antibody meditated immunity but also as a conformational control element. Together, our results demonstrate this highly dynamic conformational machine is responsive to glycan modification with implications in viral escape and vaccine design.Competing Interest StatementThe authors have declared no competing interest.View Full Text

    N-glycosylation network construction and analysis to modify glycans on the spike S glycoprotein PROTEIN of SARS-CoV-2.

    Authors: Sridevi Krishnan; Giri P Krishnan

    doi:10.1101/2020.06.23.167791 Date: 2020-06-24 Source: bioRxiv

    Background The spike S-protein PROTEIN S-protein HGNC of SARS-CoV-2 is N-glycosylated. The N-glycan structure and composition of this glycoprotein influence how the virus interacts with host cells.Objective To identify a putative N-glycan biosynthesis pathway of SARS-CoV-2 (HEK293 cell recombinant) from previously published mass spectrometric studies, and to identify what effect blocking some enzymes has on the overall glycoprotein profile. Finally, our goal was to provide the biosynthesis network, and glycans in easy-to-use format for further glycoinformatics work.Methods We reconstructed the glycosylation network based on previously published empirical data using GNAT HGNC, a glycosylation network analysis tool. Our compilation of the network tool had 23 glycosyltransferase and glucosidase enzymes, and could infer the pathway of glycosylation machinery based on glycans identified in the virus spike protein PROTEIN. Once the glycan biosynthesis pathway was generated, we simulated the effect of blocking specific enzymes - Mannosidase-II and alpha-1,6-fucosyltransferase HGNC to see how they would affect the biosynthesis network.Results Of the 23 enzymes, a total of 12 were involved in glycosylation of SARS-CoV-2 - Man-Ia, MGAT1 HGNC, MGAT2 HGNC, MGAT4, MGAT5 HGNC, B4GalT HGNC, B4GalT HGNC, Man II HGNC, SiaT, ST3GalI HGNC, ST3GalVI HGNC and FucT8. Blocking enzymes resulted in a substantially modified glycan profile of the protein.Conclusions A network analysis of N-glycan biosynthesis of SARS-CoV-2 spike PROTEIN SARS-CoV-2 spike MESHD protein shows an elaborate enzymatic pathway with several intermediate glycans, along with the ones identified by mass spectrometric studies. Variations in the final N-glycan profile of the virus, given its site-specific microheterogeneity, could be a factor in the host response to the infection and response to antibodies. Here we provide all the resources generated - the glycans derived from mass spectrometry and intermediate glycans in glycoCT xml format, and the biosynthesis network for future drug and vaccine development work.Competing Interest StatementThe authors have declared no competing interest.View Full Text

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins

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