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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.

    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.

    An In-Silico Study on Selected Organosulfur Compounds as Potential Drugs for SARS-CoV-2 Infection MESHD via Binding Multiple Drug Targets

    Authors: Liya Thurakkal; Satyam Singh; Sushabhan Sadhukhan; Mintu Porel

    doi:10.26434/chemrxiv.12505343.v1 Date: 2020-06-19 Source: ChemRxiv

    The emerging paradigm shift from ‘one molecule, one target, for one disease’ towards ‘multi-targeted small molecules’ has paved an ingenious pathway in drug discovery in recent years. This idea has been extracted for the investigation of competent drug molecules for the unprecedented COVID-19 pandemic MESHD COVID-19 pandemic MESHD which became the greatest global health crisis now. Perceiving the importance of organosulfur compounds against SARS-CoV-2 from the drugs under clinical trials, a class of organosulfur compounds effective against SARS-CoV were selected and studied the interaction with multiple proteins of the SARS-CoV-2. One compound displayed inhibition against five proteins (both structural and non-structural) of the virus namely, main protease PROTEIN, papain-like protease PROTEIN, spike protein PROTEIN, helicase HGNC and RNA dependent RNA polymerase PROTEIN. Consequently, this compound emanates as a potential candidate for treating the virulent disease. The pharmacokinetics, ADMET properties and target prediction studies carried out in this work further inflamed the versatility of the compound and urge to execute in-vitro and in-vivo analysis on SARS-CoV-2 in the future.

    Binding Mechanism and Structural Insights into the Identified Protein Target of Covid-19 MESHD with In-Vitro Effective Drug Ivermectin

    Authors: Parth Sarthi Sen Gupta; Satyaranjan Biswal; Saroj Kumar Panda; Abhik Kumar Ray; Malay Kumar Rana

    doi:10.26434/chemrxiv.12463946.v1 Date: 2020-06-12 Source: ChemRxiv

    While an FDA approved drug Ivermectin was reported to dramatically reduce the cell line of SARS-CoV-2 by ~5000 folds within 48 hours, the precise mechanism of action and the COVID-19 MESHD molecular target involved in interaction with this in-vitro effective drug are unknown yet. Among 12 different COVID-19 MESHD targets studied here, the RNA dependent RNA polymerase PROTEIN ( RdRp PROTEIN) with RNA and Helicase HGNC NCB site show the strongest affinity to Ivermectin amounting -10.4 kcal/mol and -9.6 kcal/mol, respectively. Molecular dynamics of corresponding protein-drug complexes reveals that the drug bound state of RdRp PROTEIN with RNA has better structural stability than the Helicase HGNC NCB site, with MM/PBSA free energy of -135.2 kJ/mol, almost twice that of Helicase HGNC (-76.6 kJ/mol). The selectivity of Ivermectin to RdRp PROTEIN is triggered by a cooperative interaction of RNA- RdRp PROTEIN by ternary complex formation. Identification of the target and its interaction profile with Ivermectin can lead to more powerful drug designs for COVID-19 MESHD and experimental exploration.

    Temporal evolution and adaptation of SARS-COV 2 codon usage

    Authors: Maddalena Dilucca; Sergio Forcelloni; Andrea Giansanti; Alexandros Georgakilas; Athanasia Pavlopoulou

    doi:10.1101/2020.05.29.123976 Date: 2020-06-03 Source: bioRxiv

    The outbreak of severe acute respiratory syndrome-coronavirus-2 MESHD (SARS-CoV-2) has caused an unprecedented pandemic. Since the first sequenced whole-genome of SARS-CoV-2 on January 2020, the identification of its genetic variants has become crucial in tracking and evaluating their spread across the globe. In this study, we compared 15,259 SARS-CoV-2 genomes isolated from 60 countries since the outbreak of this novel coronavirus with the first sequenced genome in Wuhan to quantify the evolutionary divergence of SARS-CoV-2. Thus, we compared the codon usage patterns, every two weeks, of 13 of SARS-CoV-2 genes encoding for the membrane protein (M PROTEIN), envelope (E), spike surface glycoprotein (S PROTEIN), nucleoprotein (N PROTEIN), non-structural 3C-like proteinase ( 3CLpro PROTEIN), ssRNA-binding protein ( RBP HGNC), 2-O-ribose methyltransferase (OMT), endoRNase (RNase), helicase HGNC, RNA-dependent RNA polymerase PROTEIN ( RdRp PROTEIN), Nsp7, Nsp8, and exonuclease ExoN. As a general rule, we find that SARS-CoV-2 genome tends to diverge over time by accumulating mutations on its genome and, specifically, on the coding sequences for proteins N PROTEIN and S. Interestingly, different patterns of codon usage were observed among these genes. Genes S, Nsp7, NSp8, tend to use a norrower set of synonymous codons that are better optimized to the human host. Conversely, genes E PROTEIN and M consistently use a broader set of synonymous codons, which does not vary with respect to the reference genome. We identified key SARS-CoV-2 genes (S, N, ExoN, RNase, RdRp PROTEIN, Nsp7 and Nsp8) suggested to be causally implicated in the virus adaptation to the human host.

    In silico Proteome analysis of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)

    Authors: Chittaranjan Baruah; Papari Devi; Dhirendra K Sharma

    doi:10.1101/2020.05.23.104919 Date: 2020-05-24 Source: bioRxiv

    Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (2019-nCoV), is a positive-sense, single-stranded RNA coronavirus. The virus is the causative agent of coronavirus disease 2019 MESHD ( COVID-19 MESHD) and is contagious through human-to-human transmission. The present study reports sequence analysis, complete coordinate tertiary structure prediction and in silico sequence-based and structure-based functional characterization of full SARS-CoV-2 proteome based on the NCBI reference sequence NC_045512 (29903 bp ss-RNA) which is identical to GenBank entry MN908947 and MT415321. The proteome includes 12 major proteins namely orf1ab polyprotein (includes 15 proteins), surface glycoprotein, ORF3a PROTEIN protein, envelope PROTEIN envelope protein HGNC, membrane glycoprotein PROTEIN, ORF6 PROTEIN protein, ORF7a PROTEIN protein, orf7b, ORF8 PROTEIN, Nucleocapsid phosphoprotein and ORF10 PROTEIN protein. Each protein of orf1ab polyprotein group has been studied separately. A total of 25 polypeptides have been analyzed out of which 15 proteins are not yet having experimental structures and only 10 are having experimental structures with known PDB IDs MESHD. Out of 15 newly predicted structures six (6) were predicted using comparative modeling and nine (09) proteins having no significant similarity with so far available PDB structures were modeled using ab-initio modeling. Structure verification using recent tools QMEANDisCo 4.0.0 and ProQ3 for global and local (per-residue) quality estimates indicate that the all-atom model of tertiary structure of high quality and may be useful for structure-based drug designing targets. The study has identified nine major targets ( spike protein PROTEIN, envelop protein, membrane protein, nucleocapsid PROTEIN protein, 2-O-ribose methyltransferase, endoRNAse, 3-to-5 exonuclease, RNA-dependent RNA polymerase PROTEIN and helicase HGNC) for which drug design targets could be considered. There are other 16 nonstructural proteins PROTEIN (NSPs), which may also be percieved from the drug design angle. The protein structures have been deposited to ModelArchive. Tunnel analysis revealed the presence of large number of tunnels in NSP3 HGNC NSP3 PROTEIN, ORF 6 protein and membrane glycoprotein PROTEIN indicating a large number of transport pathways for small ligands influencing their reactivity.

    Two mutations P/L and Y/C in SARS-CoV-2 helicase HGNC domain exist together and influence helicase HGNC RNA binding

    Authors: Feroza Begum; Arup Kumar Banerjee; Prem Prakash Tripathi; UPASANA RAY

    doi:10.1101/2020.05.14.095224 Date: 2020-05-15 Source: bioRxiv

    RNA helicases play pivotal role in RNA replication by catalysing the unwinding of complex RNA duplex structures into single strands in ATP/NTP dependent manner. SARS coronavirus 2 (SARS-CoV-2) is a single stranded positive sense RNA virus belonging to the family Coronaviridae. The viral RNA encodes non structural protein Nsp13 or the viral helicase HGNC protein that helps the viral RNA dependent RNA polymerase PROTEIN ( RdRp PROTEIN) to execute RNA replication by unwinding the RNA duplexes. In this study we identified a novel mutation at position 541of the helicase HGNC where the tyrosine (Y) got substituted with cytosine (C). We found that Y541C is a destabilizing mutation increasing the molecular flexibility and leading to decreased affinity of helicase HGNC binding with RNA. Earlier we had reported a mutation P504L in the helicase HGNC protein for which had not performed RNA binding study. Here we report that P504L mutation leads to increased affinity of helicase HGNC RNA interaction. So, both these mutations have opposite effects on RNA binding. Moreover, we found a significant fraction of isolate population where both P504L and Y541C mutations were co-existing.

    Specific mutations in SARS-CoV2 RNA dependent RNA polymerase PROTEIN and helicase HGNC alter protein structure, dynamics and thus function: Effect on viral RNA replication


    doi:10.1101/2020.04.26.063024 Date: 2020-04-27 Source: bioRxiv

    1.The open reading frame PROTEIN (ORF) 1ab of SARS-CoV2 encodes non-structural proteins involved in viral RNA functions like translation and replication including nsp1-4; 3C like proteinase; nsp6-10; RNA dependent RNA polymerase PROTEIN ( RdRp PROTEIN); helicase HGNC and 3-5 exonuclease. Sequence analyses of ORF1ab PROTEIN unravelled emergence of mutations especially in the viral RdRp PROTEIN and helicase HGNC at specific positions, both of which are important in mediating viral RNA replication. Since proteins are dynamic in nature and their functions are governed by the molecular motions, we performed normal mode analyses of the SARS-CoV2 wild type and mutant RdRp PROTEIN and helicases to understand the effect of mutations on their structure, conformation, dynamics and thus function. Structural analyses revealed that mutation of RdRp PROTEIN (at position 4715 in the context of the polyprotein/ at position 323 of RdRp PROTEIN) leads to rigidification of structure and that mutation in the helicase HGNC (at position 5828 of polyprotein/ position 504) leads to destabilization increasing the flexibility of the protein structure. Such structural modifications and protein dynamics alterations might alter unwinding of complex RNA stem loop structures, the affinity/ avidity of polymerase RNA interactions and in turn the viral RNA replication. The mutation analyses of proteins of the SARS-CoV2 RNA replication complex would help targeting RdRp PROTEIN better for therapeutic intervention.

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins

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