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    Repurposing Multi-Targeting Plant Natural Product Scaffolds In Silico Against SARS-CoV- 2 Non-Structural Proteins PROTEIN Implicated in Viral Pathogenesis

    Authors: Von Novi de Leon; Joe Anthony Manzano; Delfin Yñigo H. Pilapil; Rey Arturo T. Fernandez; James Kyle Ching; Mark Tristan J. Quimque; Kin Israel Notarte; Allan Patrick Macabeo

    doi:10.26434/chemrxiv.14125433.v1 Date: 2021-03-01 Source: ChemRxiv

    Background: Accessing COVID-19 MESHD vaccines is a challenge despite successful clinical trials. This burdens the COVID-19 MESHD treatment gap, thereby requiring accelerated discovery of anti-SARS-CoV-2 agents. Thus, this study explored the potential of anti-HIV reverse transcriptase (RT) phytochemicals as inhibitors of SARS-CoV- 2 non-structural proteins PROTEIN (nsps) by targeting in silico key sites in the structures of SARS-CoV-2 nsps. Moreover, structures of the anti-HIV compounds were considered for druggability and toxicity MESHD. 104 anti-HIV phytochemicals were subjected to molecular docking with papain-like protease PROTEIN ( nsp3 HGNC), 3-chymotrypsin-like protease ( nsp5 HGNC), RNA-dependent RNA polymerase PROTEIN (nsp12), helicase HGNC (nsp13), SAM-dependent 2’-O-methyltransferase (nsp16) and its cofactor (nsp10), and endoribonuclease (nsp15). Drug-likeness MESHD and ADME (absorption, distribution, metabolism, and excretion) properties of the top ten compounds per nsp were predicted using SwissADME. Their toxicity MESHD was also determined using OSIRIS Property Explorer. Results: Among the twenty-seven top-scoring compounds, the polyphenolic natural products amentoflavone (1), robustaflavone (4), punicalin (9), volkensiflavone (11), rhusflavanone (13), morelloflavone (14), hinokiflavone (15), and michellamine B (19) were multi-targeting and had the strongest affinities to at least two of the nsps (Binding Energy = -7.7 to -10.8 kcal/mol). Friedelin (2), pomolic acid (5), ursolic acid (10), garcisaterpenes A (12), hinokiflavone (15), and digitoxigenin-3-O-glucoside (17) were computationally druggable. Moreover, compounds 5 and 17 showed good gastrointestinal absorptive property. Most of the compounds were also predicted to be non-toxic. Conclusions: Twenty anti-HIV RT phytochemicals showed multi-targeting inhibitory potential against SARS-CoV-2 nsp3 HGNC, 5, 10, 12, 13, 15, and 16, and can therefore be used as prototypes for anti- COVID-19 MESHD drug design.

    Evolving Infection Paradox of SARS-CoV-2: Fitness Costs Virulence?

    Authors: A. S. M. Rubayet Ul Alam; Ovinu Kibria Islam; Md. Shazid Hasan; Mir Raihanul Islam; Shafi Mahmud; Hassan M. AlEmran; Iqbal K Jahid; Keith A. Crandall; M. Anwar Hossain

    doi:10.1101/2021.02.21.21252137 Date: 2021-02-23 Source: medRxiv

    Background: SARS-CoV-2 is continuously spreading worldwide at an unprecedented scale and evolved into seven clades according to GISAID where four (G, GH, GR and GV) are globally prevalent in 2020. These major predominant clades of SARS-CoV-2 are continuously increasing COVID-19 MESHD cases worldwide; however, after an early rise in 2020, the death-case ratio has been decreasing to a plateau. G clade viruses contain four co-occurring mutations in their genome (C241T+C3037T+C14408T: RdRp PROTEIN.P323L+A23403G:spike.D614G). GR, GH, and GV strains are defined by the presence of these four mutations in addition to the clade-featured mutation in GGG28881-28883AAC:N. RG203-204KR, G25563T: ORF3a PROTEIN.Q57H, and C22227T:spike.A222V+C28932T-N.A220V+G29645T, respectively. The research works are broadly focused on the spike protein PROTEIN mutations that have direct roles in receptor binding, antigenicity, thus viral transmission and replication fitness. However, mutations in other proteins might also have effects on viral pathogenicity and transmissibility. How the clade-featured mutations are linked with viral evolution in this pandemic through gearing their fitness MESHD and virulence is the main question of this study. Methodology: We thus proposed a hypothetical model, combining a statistical and structural bioinformatics approach, endeavors to explain this infection paradox by describing the epistatic effects of the clade-featured co-occurring mutations on viral fitness MESHD and virulence. Results and Discussion: The G and GR/GV clade strains represent a significant positive and negative association, respectively, with the death-case ratio (incidence rate ratio or IRR = 1.03, p <0.001 and IRR= 0.99/0.97, p < 0.001), whereas GH clade strains showed no association with the Docking analysis showed the higher infectiousness of a spike mutant through more favorable binding of G614 with the elastase-2 HGNC. RdRp PROTEIN mutation p.P323L significantly increased genome-wide mutations (p<0.0001) since more expandable RdRp PROTEIN (mutant)- NSP8 PROTEIN interaction may accelerate replication. Superior RNA stability and structural variation at NSP3 HGNC NSP3 PROTEIN:C241T might impact upon protein or RNA interactions. Another silent 5'UTR:C241T mutation might affect translational efficiency and viral packaging. These G-featured co-occurring mutations might increase the viral load, alter immune responses in host and hence can modulate intra-host genomic plasticity. An additional viroporin ORF3a PROTEIN:p.Q57H mutation, forming GH-clade, prevents ion permeability by cysteine (C81)-histidine (H57) inter-transmembrane-domain interaction mediated tighter constriction of the channel pore and possibly reduces viral release and immune response. GR strains, four G clade mutations and N:p.RG203-204KR, would have stabilized RNA interaction by more flexible and hypo-phosphorylated SR-rich region. GV strains seemingly gained the evolutionary advantage of superspreading event through confounder factors; nevertheless, N:p.A220V might affect RNA binding. Conclusion: These hypotheses need further retrospective and prospective studies to understand detailed molecular and evolutionary events featuring the fitness MESHD and virulence of SARS-CoV-2.

    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.

    Comparative analysis of loop-mediated isothermal amplification (LAMP)-based assays for rapid detection of SARS-CoV-2 genes

    Authors: Daniel Urrutia-Cabrera; Roxanne Hsiang-Chi Liou; Jianxiong Chan; Sandy Shen-Chi Hung; Alex W Hewitt; Keith Martin; Patrick Kwan; Raymond Ching-Bong Wong

    doi:10.1101/2020.12.21.20248288 Date: 2020-12-22 Source: medRxiv

    The COVID-19 pandemic MESHD caused by SARS-CoV-2 has infected millions worldwide and there is an urgent need to increase our diagnostic capacity to identify infected cases. Although RT-qPCR remains the gold standard for SARS-CoV-2 detection, this method requires specialised equipment in a diagnostic laboratory and has a long turn-around time to process the samples. To address this, several groups have recently reported development of loop-mediated isothermal amplification (LAMP) as a simple, low cost and rapid method for SARS-CoV-2 detection. Herein we present a comparative analysis of three LAMP-based assays that target different regions of the SARS-CoV-2: ORF1ab PROTEIN RdRP PROTEIN, ORF1ab PROTEIN nsp3 HGNC and Gene N PROTEIN. We perform a detailed assessment of their sensitivity, kinetics and false positive rates for SARS-CoV-2 diagnostics in LAMP or RT-LAMP reactions, using colorimetric or fluorescent detection. Our results independently validate that all three assays can detect SARS-CoV-2 in 30 minutes, with robust accuracy at detecting as little as 1000 RNA copies and the results can be visualised simply by color changes. We also note the shortcomings of these LAMP-based assays, including variable results with shorter reaction time or lower load of SARS-CoV-2, and false positive results in some experimental conditions. Overall for RT-LAMP detection, the ORF1ab PROTEIN RdRP PROTEIN and ORF1ab PROTEIN nsp3 HGNC assays have higher sensitivity and faster kinetics for detection, whereas the Gene N PROTEIN assay exhibits no false positives in 30 minutes reaction time. This study provides validation of the performance of LAMP-based assays for SARS-CoV-2 detection, which have important implications in development of point-of-care diagnostic for SARS-CoV-2.

    Computational Analysis of Dynamic Allostery and Control in the three SARS-CoV- 2 non-structural proteins PROTEIN

    Authors: Igors Dubanevics; Charles Heaton; Carlos Riechmann; Tom C B McLeish; Theresa A Ramelot; Thomas B. Acton; Elena Moreno; Thomas Kehrer; Catherine A. Royer; Adolfo Garcia-Sastre; Robert M Krug; Gaetano T. Montelione

    doi:10.1101/2020.12.12.422477 Date: 2020-12-14 Source: bioRxiv

    Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which caused the COVID-19 pandemic MESHD, has no vaccine or antiviral drugs available to the public, at the time of writing. The virus non-structural proteins are promising drug targets because of their vital role in the viral cycle. A significant body of work has been focused on finding inhibitors which covalently and competitively bind the active site of the non-structural proteins, but little has been done to address regions other than the active site, i.e. for non-competitive inhibition. Here we extend previous work on the SARS-CoV-2 Mpro PROTEIN ( nsp5 HGNC) to three other SARS-CoV-2 proteins: host shutoff factor PROTEIN ( nsp1 HGNC), papain-like protease PROTEIN ( nsp3 HGNC, also known as PLpro PROTEIN) and RNA-dependent RNA-polymerase PROTEIN (nsp12, also known as RdRp) in complex PROTEIN with nsp7 and nsp8 cofactors. Using open-source software (DDPT) to construct Elastic Network Models (ENM) of the chosen proteins we analyse their fluctuation dynamics and thermodynamics, as well as using this protein family to study convergence and robustness of the ENM. Exhaustive 2-point mutational scans of the ENM and their effect on fluctuation free energies suggest several new candidate regions, distant from the active site, for control of the proteins function, which may assist the drug development based on the current small molecule binding screens. The results also provide new insights, including non-additive effects of double-mutation or inhibition, into the active biophysical research field of protein fluctuation allostery and its underpinning dynamical structure.

    Drug Design and Repurposing with DockThor-VS Web Server: Virtual Screening focusing on SARS-CoV-2 Therapeutic Targets and their Non-Synonym Variants

    Authors: Isabella A. Guedes; Leon S. C. Costa; Karina B. dos Santos; Ana L. M. Karl; Gregório K. Rocha; Iury M. Teixeira; Marcelo M. Galheigo; Vivian Medeiros; Eduardo Krempser; Fábio L. Custódio; Helio J. C. Barbosa; Marisa F. Nicolás; Laurent E. Dardenne

    doi:10.21203/rs.3.rs-96789/v1 Date: 2020-10-22 Source: ResearchSquare

    The COVID-19 MESHD caused by the SARS-CoV-2 virus was declared as a pandemic disease in March 2020 by the World Health Organization (WHO). Structure-Based Drug Design strategies based on docking methodologies have been widely used for both new drug development and drug repurposing to find effective treatments against this disease. In this work, we present the developments implemented in the DockThor-VS web server to provide a virtual screening (VS) platform with curated structures of potential therapeutic targets from SARS-CoV-2 incorporating genetic information regarding relevant non-synonymous variations. The web server facilitates repurposing VS experiments providing curated libraries of currently available drugs on the market. Currently, DockThor-VS provides ready-for-docking 3D structures for wild type and selected mutations for Nsp3 HGNC (papain-like, PLpro PROTEIN domain), Nsp5 HGNC ( Mpro PROTEIN, 3CLpro PROTEIN), Nsp12 ( RdRp PROTEIN), Nsp15 (NendoU), N protein PROTEIN and Spike. We performed VS experiments of FDA-approved drugs considering the therapeutic targets available at the web server to assess the impact of considering different structures and mutations in the identification of possible new treatments of SARS-CoV-2 infections MESHD. The DockThor-VS is freely available at www.dockthor.lncc.br.

    Temporal landscape of mutation accumulation in SARS-CoV-2 genomes from Bangladesh: possible implications from the ongoing outbreak in Bangladesh

    Authors: Otun Saha; Rokaiya Nurani Shatadru; Nadira Naznin Rakhi; Israt Islam; Md. Shahadat Hossain; Md. Mizanur Rahaman; Leo C James; Madeline A Lancaster; Zhu Shu; Zhiming Yuan; Lei Tong; Han Xia; Jingzhe Pan; Natalie Garton; Manish Pareek; Michael Barer; Craig J Smith; Stuart M Allan; Michelle M. Lister; Hannah C. Howson-Wells; Edward C Holmes; Matthew W. Loose; Jonathan K. Ball; C. Patrick McClure; - The COVID-19 Genomics UK consortium study group; Shi Chen

    doi:10.1101/2020.08.20.259721 Date: 2020-08-21 Source: bioRxiv

    Along with intrinsic evolution, adaptation to selective pressure in new environments might have resulted in the circulatory SARS-CoV-2 strains in response to the geoenvironmental conditions of a country and the demographic profile of its population. Thus the analysis of genomic mutations of these circulatory strains may give an insight into the molecular basis of SARS-CoV-2 pathogenesis and evolution favoring the development of effective treatment and containment strategies. With this target, the current study traced the evolutionary route and mutational frequency of 198 Bangladesh originated SARS-CoV-2 genomic sequences available in the GISAID platform over a period of 13 weeks as of 14 July 2020. The analyses were performed using MEGA 7, Swiss Model Repository, Virus Pathogen Resource and Jalview visualization. Our analysis identified that majority of the circulating strains in the country belong to B and/or L type among cluster A to Z and strikingly differ from both the reference genome and the first sequenced genome from Bangladesh. Mutations in Nonspecific protein 2 ( NSP2 PROTEIN NSP2 HGNC), NSP3 PROTEIN NSP3 HGNC, RNA dependent RNA polymerase PROTEIN ( RdRp PROTEIN), Helicase HGNC, Spike, ORF3a PROTEIN, and Nucleocapsid (N) protein PROTEIN were common in the circulating strains with varying degrees and the most unique mutations(UM) were found in NSP3 HGNC NSP3 PROTEIN (UM-18). But no or limited changes were observed in NSP9 PROTEIN, NSP11 PROTEIN, E (Envelope), NSP7a, ORF 6, and ORF 7b suggesting the possible conserved functions of those proteins in SARS-CoV-2 propagation. However, along with D614G mutation, more than 20 different mutations in the Spike protein PROTEIN were detected basically in the S2 domain. Besides, mutations in SR-rich region of N protein PROTEIN and P323L in RDRP PROTEIN were also present. However, the mutation accumulation showed an association with sex and age of the COVID-19 MESHD positive cases. So, identification of these mutational accumulation patterns may greatly facilitate drug/ vaccine development deciphering the age and the sex dependent differential susceptibility to COVID-19 MESHD.

    The genetic variants analysis of circulating SARS-CoV-2 in Bangladesh.

    Authors: Abu Sayeed Mohammad Mahmud; Tarannum Taznin; Md. Murshed Hasan Sarkar; Mohammad Samir Uzzaman; Eshrar Osman; Md. Ahasan Habib; Shahina Akter; Tanjina Akhter Banu; Barna Goswami; Iffat Jahan; Md. Saddam Hossain; Md. Salim Khan

    doi:10.1101/2020.07.29.226555 Date: 2020-07-29 Source: bioRxiv

    Genomic mutation of the virus may impact the viral adaptation to the local environment, their transmission, disease manifestation, and the effectiveness of existing treatment and vaccination. The objectives of this study were to characterize genomic variations, non-synonymous amino acid substitutions, especially in target proteins, mutation events per samples, mutation rate, and overall scenario of coronaviruses across the country. To investigate the genetic diversity, a total of 184 genomes of virus strains sampled from different divisions of Bangladesh with sampling dates between the 10th of May 2020 and the 27th of June 2020 were analyzed. To date, a total of 634 mutations located along the entire genome resulting in non-synonymous 274 amino acid substitutions in 22 different proteins were detected with nucleotide mutation rate estimated to be 23.715 substitutions per year. The highest non-synonymous amino acid substitutions were observed at 48 different positions of the papain-like protease PROTEIN ( nsp3 HGNC). Although no mutations were found in nsp7, nsp9, nsp10, and nsp11, yet orf1ab accounts for 56% of total mutations. Among the structural proteins, the highest non-synonymous amino acid substitution (at 36 positions) observed in spike proteins PROTEIN, in which 9 unique locations were detected relative to the global strains, including 516E>Q in the boundary of the ACE2 HGNC binding region. The most dominated variant G614 (95%) based in spike protein PROTEIN is circulating across the country with co-evolving other variants including L323 (94%) in RNA dependent RNA polymerase PROTEIN ( RdRp PROTEIN), K203 (82%) and R204 (82%) in nucleocapsid, and F120 (78%) in NSP2 PROTEIN NSP2 HGNC. These variants are mostly seen as linked mutations and are part of a haplotype observed in Europe. Data suggest effective containment of clade G strains (4.8%) with sub-clusters GR 82.4%, and GH clade 6.4%. HighlightsO_LIWe have sequenced 137 and analyzed 184 whole-genomes sequences of SARS-CoV-2 strains from different divisions of Bangladesh. C_LIO_LIA total of 634 mutation sites across the SARS-CoV-2 genome and 274 non-synonymous amino acid substitutions were detected. C_LIO_LIThe mutation rate of SARS-CoV-2 estimated to be 23.715 nucleotide substitutions per year. C_LIO_LINine unique variants were detected based on non-anonymous amino acid substitutions in spike protein PROTEIN relative to the global SARS-CoV-2 strains. C_LI

    Comprehensive analysis of genomic diversity of SARS-CoV-2 in different geographic regions of India: An endeavour to classify Indian SARS-CoV-2 strains on the basis of co-existing mutations

    Authors: Rakesh Sarkar; Suvrotoa Mitra; Pritam Chandra; Priyanka Saha; Anindita Banerjee; Shanta Dutta; Mamta Chawla-Sarkar

    doi:10.1101/2020.07.14.203463 Date: 2020-07-15 Source: bioRxiv

    Accumulation of mutations within the genome is the primary driving force for viral evolution within an endemic setting. This inherent feature often leads to altered virulence, infectivity and transmissibility as well as antigenic shift to escape host immunity, which might compromise the efficacy of vaccines and antiviral drugs. Therefore, we aimed at genome-wide analyses of circulating SARS-CoV-2 viruses for the emergence of novel co-existing mutations and trace their spatial distribution within India. Comprehensive analysis of whole genome sequences of 441 Indian SARS-CoV-2 strains revealed the occurrence of 33 different mutations, 21 being distinctive to India. Emergence of novel mutations were observed in S glycoprotein PROTEIN (7/33), NSP3 HGNC NSP3 PROTEIN (6/33), RdRp PROTEIN/ NSP12 PROTEIN (4/33), NSP2 PROTEIN NSP2 HGNC (2/33) and N (2/33). Non-synonymous mutations were found to be 3.4 times more prevalent than synonymous mutations. We classified the Indian isolates into 22 groups based on the co-existing mutations. Phylogenetic analyses revealed that representative strain of each group divided themselves into various sub-clades within their respective clades, based on the presence of unique co-existing mutations. India was dominated by A2a clade (55.60%) followed by A3 (37.38%) and B (7%), but exhibited heterogeneous distribution among various geographical regions. The A2a clade mostly predominated in East India, Western India and Central India, whereas A3 clade prevailed in South and North India. In conclusion, this study highlights the divergent evolution of SARS-CoV-2 strains and co-circulation of multiple clades in India. Monitoring of the emerging mutations would pave ways for vaccine formulation and designing of antiviral drugs.

    Dynamic tracking of variant frequencies depicts the evolution of mutation sites amongst SARS-CoV-2 genomes from India

    Authors: Gaurav Sharma; Vaishnavi Kolte; Shenu Hudson B.; Azra Khan

    doi:10.1101/2020.07.14.201905 Date: 2020-07-14 Source: bioRxiv

    With the exponential spread of COVID-19 MESHD COVID-19 MESHD pandemic across the world within the last six months, SARS-CoV-2 strains are continuously trying to adapt themselves in their host environment by random mutations. While doing so, some variants with evolutionary advantages such as better human to human transmissibility potential should get naturally selected. This short communication demonstrates how the mutation probability patterns are evolving in 864 SAR-CoV-2 strains isolated from COVID-19 MESHD patients across diverse Indian states. We have identified 30 such variants showing contrasting mutational probabilities in the span of four months. Out of these, the mutational probabilities of 25 variants including C14408T (in RdRp PROTEIN gene), A23403G (in spike gene), C6312A ( nsp3 HGNC gene) are continuously increasing suggesting that these mutations are being propagated with time due to their unexplored evolutionary advantages. In contrast, the mutational probabilities of five variants including C6312A ( nsp3 HGNC gene), G11083T (nsp6 gene), C28311T ( N gene PROTEIN) have significantly decreased in May-June as compared to March-April, suggesting these mutations are being terminated with time. Further in-depth investigation of these identified variants will provide valuable knowledge about the evolution, infection strategies, transmission rates, and epidemiology of SARS-CoV-2 in India.

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins

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