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    Investigation of Anti-Coronavirus, Anti-HCV, Nucleotide Inhibitors, and Bioactive Molecules efficacy Against RNA-directed RNA polymerase of Nipah Virus: Molecular Docking Study

    Authors: Peter T. Habib

    doi:10.21203/rs.3.rs-294115/v2 Date: 2021-03-03 Source: ResearchSquare

    The infections with the Nipah virus (NiV) are highly infectious and may lead to severe febrile encephalitis MESHD. High rates of mortality in southeastern Asia including Bengal, Malaysia, Papua New Guinea, Vietnam, Cambodia, Indonesia, Madagascar, the Philippines, Thailand, and India have been reported in NiV outbreaks. Considering the high risk of an epidemic, NiV was declared a priority pathogen by the World Health Organization (WHO). However, for the treatment of this infection, there is no effective therapy or approved FDA medicines. RNA-dependent polymerase RNA PROTEIN ( RdRp PROTEIN) plays an important role in viral replication among the nine well-known proteins of NiV. Therefore, fourteen antiviral molecules have been computerized for NiV RNA-dependent RNA polymerase PROTEIN and demonstrated a potential inhibition effect against coronavirus (NiV- RdRp PROTEIN). A multi-step molecular docking process, followed by extensive analyzes of molecular binding interactions, binding energy estimates, synthetic accessibility assessments, and toxicity MESHD tests. Analysis reveals that Uprifosbuvir is the most suitable inhibitor for RdRp PROTEIN of Nipah Virus regarding the binding affinity and binding in the target cavity. Although, such studies need clinical confirmation.

    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.

    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.

    In Vitro: Natural Compounds (Thymol, Carvacrol, Hesperidine, And Thymoquinone) Against Sars-Cov2 Strain Isolated From Egyptian Patients

    Authors: Mohamed G Seadawy; Ahmed F. Gad; Mohamed Shamel; Bassem Elharty; Mostfa F. Mohamed; Abdo A. Elfiky; Aya Ahmed; Abdel Rahman N. Zekri

    doi:10.21203/rs.3.rs-119568/v1 Date: 2020-12-01 Source: ResearchSquare

    Background: The current pandemic of the coronavirus disease-2019 ( COVID-19 MESHD) has badly affected our life during the year 2020. SARS-CoV-2 is the primary causative agent of the newly emerged pandemic. Natural flavonoids, Terpenoid and Thymoquinone are tested against different viral and host-cell protein targets. These natural compounds have a good history in treating Hepatitis C Virus MESHD ( HCV MESHD) and Human Immunodeficiency Virus (HIV) MESHD. Methods: Molecular docking combined with cytotoxicity MESHD and plaque reduction assay is used to test the natural compounds against different viral (Spike, RdRp PROTEIN, and Mpro PROTEIN) and host-cell (TMPRSS II, keap 1 HGNC, and ACE2 HGNC) targets. Results: The results demonstrate the binding possibility of the natural compounds (Thymol, Carvacrol, Hesperidine, and Thymoquinone) to the viral main protease PROTEIN ( Mpro PROTEIN). Some of these natural compounds were approved to start clinical trail from Egypt Center for Research and Regenerative Medicine ECRRM IRB (Certificate No.IRB00012517)Conclusion: Development of an effective anti-viral for SARS-CoV-2  could help to limit the viral load. Benchmarking testing of those natural compounds against other potential antivirals for SARS-CoV-2 with alternative mechanisms of action would thus be important as soon as practicable.

    in vitro: Natural Compounds (Thymol, Carvacrol, Hesperidine, And Thymoquinone) Against SARS-CoV2 Strain Isolated From Egyptian Patients

    Authors: Mohamed Gomaa Seadawy; Ahmed F Gad; Bassem E Harty; Mostfa Fetooh Mohamed; Mohamed Shamel ELdesoky; Abdo A Elfiky; Aya Ahmed; Abdel N Zekri; Elitza S Theel; Ali H Ellebedy; Daved H Fremont; Michael S Diamond; Sean P. J. Whelan; Gius Kerster; Hannah L Turner; Karlijn van der Straten; Cynthia A. van der Linden; Yoann Aldon; Thibaut Naninck; Ilja Bontjer; Judith A. Burger; Meliawati Poniman; Anna Z Mykytyn; Nisreen M.A. Okba; Edith E. Schermer; Marielle J. van Breemen; Rashmi Ravichandran; Tom G. Caniels; Jelle van Schooten; Nidhal Kahlaoui; Vanessa Contreras; Julien Lemaitre; Catherine Chapon; Raphael Ho Tsong Fang; Julien Villaudy; Kwinten Sliepen; Yme U. van der Velden; Bart Haagmans; Godelieve J. de Bree; Eric Ginoux; Andrew B. Ward; Max Crispin; Neil P King; Sylvie van der Werf; Marit J. van Gils; Roger Le Grand; Rogier W. Sanders

    doi:10.1101/2020.11.07.367649 Date: 2020-11-08 Source: bioRxiv

    The current pandemic of the coronavirus disease-2019 ( COVID-19 MESHD) has badly affected our life during the year 2020. SARS-CoV-2 is the primary causative agent of the newly emerged pandemic. Natural flavonoids, Terpenoid and Thymoquinone are tested against different viral and host-cell protein targets. These natural compounds have a good history in treating Hepatitis C Virus MESHD ( HCV MESHD) and Human Immunodeficiency Virus (HIV) MESHD. Molecular docking combined with cytotoxicity MESHD and plaque reduction assay is used to test the natural compounds against different viral (Spike, RdRp PROTEIN, and Mpro PROTEIN) and host-cell (TMPRSS II, keap 1 HGNC, and ACE2 HGNC) targets. The results demonstrate the binding possibility of the natural compounds (Thymol, Carvacrol, Hesperidine, and Thymoquinone) to the viral main protease PROTEIN ( Mpro PROTEIN). Some of these natural compounds were approved to start clinical trail from Egypt Center for Research and Regenerative Medicine ECRRM IRB (Certificate No.IRB00012517)

    Natural Compounds (Thymol, Carvacrol, Hesperidine, and Thymoquinone) Against SARS-CoV-2 Strain Isolated From Egyptian Patients

    Authors: Mohamed Seadawy

    doi:10.21203/rs.3.rs-101405/v1 Date: 2020-11-01 Source: ResearchSquare

    The current pandemic of the coronavirus disease-2019 ( COVID-19 MESHD) has badly affected our life during the year 2020. SARS-CoV-2 is the primary causative agent of the newly emerged pandemic. Natural flavonoids, Terpenoid and Thymoquinone are tested against different viral and host-cell protein targets. These natural compounds have a good history in treating Hepatitis C Virus MESHD ( HCV MESHD) and Human Immunodeficiency Virus (HIV) MESHD. Molecular docking combined with cytotoxicity MESHD and plaque reduction assay is used to test the natural compounds against different viral (Spike, RdRp PROTEIN, and Mpro PROTEIN) and host-cell (TMPRSS II, keap 1 HGNC, and ACE2 HGNC) targets. The results demonstrate the binding possibility of the natural compounds (Thymol, Carvacrol, Hesperidine, and Thymoquinone) to the viral main protease PROTEIN ( Mpro PROTEIN). Some of these natural compounds were approved to start clinical trail from Egypt Center for Research and Regenerative Medicine ECRRM IRB (Certificate No.IRB00012517)

    Phytochemical Compounds Present in COVI-MXG Herbal Preparation Inhibits RNA-Dependent RNA Polymerase PROTEIN from SARS-CoV-2: Virtual Screening

    Authors: Poyi, Catherine O; Falang, Kakjing D; Kolawole, Jacob A

    doi:10.21203/rs.3.rs-38115/v1 Date: 2020-06-27 Source: ResearchSquare

    Background: COVID-19 MESHD COVID-19 MESHD pandemic disease, caused by coronavirus 2 (SARS-CoV-2) is expressed as severe acute respiratory syndrome MESHD. There are currently no proven effective therapeutic agents or vaccines against the virus. However clinical management includes infection prevention, control measures, supportive care using drug therapy based on previous scientific experience, pathophysiology and pharmacology of the drug. Some of the therapeutic agents exploited include; antiviral and antimalarial agents (remdesivir, hydroxychloroquine, chloroquine, lopinavir, umifenovir, favipiravir, and oseltamivir), Zinc and selenium. There are claims of herbal preparations with palliative or therapeutic effects. The novel formulation of herbal preparation, COVI-MXG for the management of Covid-19 MESHD contains a unique combination of five (5) plants. In silico studies was carried out using robust methods and software to evaluate the plant constituents to determine its possible antiviral activity, safety and pharmacokinetic profile. Results: Pharmacokinetic predictions showed phytochemicals with varying degrees of gastrointestinal absorption rates and blood brain barrier permeability. Toxicity MESHD class fall between 3 and 5 with high LD50 values. Conclusions: When compared with the listed therapeutic agents, the phytochemical compounds present in COVI-MXG showed varying degrees of binding affinities for SARS-CoV-2 (7BV2.pdb) better than the drugs currently in use at the target sites. The preparation contains high concentration of Zinc and other micronutrients.

    Potential activity of a selected natural compounds on SARS-CoV-2 RNA-dependent-RNA polymerase PROTEIN, and binding affinity of the receptor-binding domain (RBD)

    Authors: Hisham Altayeb; Lamjed Bouslama; Jawaher Abdualbaqi Abdulhakimc; Kamel Chaieb; Othman A. S. Baothman; Mazin A. Zamzami

    doi:10.21203/rs.3.rs-32971/v1 Date: 2020-06-02 Source: ResearchSquare

    Coronavirus disease MESHD ( COVID-19 MESHD) is caused by SARS-CoV-2 and represents the causative agent of a potentially lethal disease. COVID-19 MESHD has been described as a significant global public health pandemic by the World Health Organization due to its high mortality rate, rapid spread, and the lack of drugs and vaccines for it. Active antiviral drugs are desperately needed to combat the potential return of severe acute respiratory syndrome MESHD (SARS).In this study, we selected 39 natural compounds present in plants, algae, and sponges with antiviral activity. Molecular docking was used to screen the compounds’ activity on SARS- CoV-2 RNA-dependent-RNA polymerase PROTEIN, receptor-binding domain (RBD), and the human ACE2 receptor. Compounds with binding energy ≤ -6.5 kcal/mol enter pre-clinical testing using in silco ADME/ Tox HGNC (absorption, distribution, metabolism, excretion, and toxicity MESHD).We found eight potential SARS-CoV-2 inhibitors: (glycyrrhizin, rutin, baicalin, 1, 6-di-O- galloyl-beta-D-glucose, pyropheophorbide A, pheophorbide A, beta-Sitosterol, and vitexin). These outcomes indicate that these compounds could be potential candidates to be utilized in lead optimization for the design and production of the anti-SARS-CoV-2 drug.

    Ayurveda botanicals in COVID-19 MESHD management: An in silico- multitarget approach

    Authors: Swapnil Borse; Manali Joshi; Akash Saggam; Vedika Bhat; Safal Walia; Sneha Sagar; Preeti Chavan-Gautam; Girish Tillu

    doi:10.21203/rs.3.rs-30361/v1 Date: 2020-05-19 Source: ResearchSquare

    The Coronavirus disease MESHD ( COVID-19 MESHD) caused by the virus SARS-CoV-2 has become a global pandemic in a very short time span. Currently, there is no specific treatment or vaccine to counter this highly contagiousdisease. Presently, existing anti-virals and disease-modifying agents are being repurposed to manage COVID-19 MESHD. There is an urgent need to find a specific cure for the disease and global efforts are directed at developing SARS-CoV-2 specific anti-viralsand immunomodulators.The objective of this study is to explore the immunomodulatory and anti-SARS-CoV-2 potential of key phytoconstituents from Ayurveda based Rasayana drugs, Withania somnifera (Ashwagandha), Tinospora cordifolia (Guduchi) and Asparagus racemosus (Shatavari) using in silico approaches like network pharmacology, and molecular docking. The SWISS-ADME tool was used to predict the pharmacokinetic and pharmacodynamic (PK-PD) interactions and drug likeliness potential. Using these approaches we propose a library of phytomolecules with potential to be developed as phytopharmaceuticals for COVID 19 management.The plant extracts were prepared as per Ayurvedic procedures and a total of 31 phytoconstituents were identified using HPLC and MS studies. The network pharmacology model shows that these phytoconstituents possess the potential to modulate several immune pathways. Amongst the three botanicalsWithania somnifera was found to be the most potent immunomodulator through its potential to modulate T cell differentiation, NK cell cytotoxicity MESHD as well as T cell, B cell and NOD-like receptor signalling pathways.Molecular docking studies showed thatseveral phytoconstituents possess good affinity for the Spike protein PROTEIN, Main Protease PROTEIN and RNA dependent RNA polymerase PROTEIN of SARS-CoV-2 suggesting their application for the termination of viral life cycle. Further, predictive tools indicate that there would beneficial herb-drug pharmacokinetic-pharmacodynamic interactions with concomitantly administered drug therapy. We thus make a compelling case to evaluate the potential of these Rasayana botanicals in the management of COVID-19 MESHD following rigorous experimental validation.

    Not One, But Five: Virtual Screening-Driven Drug Discovery of SARS-CoV2 Enzyme Inhibitors Targeting Viral Attachment, Replication and Post-Translational Infection Mechanisms

    Authors: Mark Tristan J. Quimque; Kin Israel Notarte; Rey Arturo T. Fernandez; Mark Andrew O. Mendoza; Rhenz Alfred D. Liman; Justin Allen K. Lim; Luis Agustin E. Pilapil; Jehiel Karsten H. Ong; Adriel M. Pastrana; Allan Patrick Macabeo

    doi:10.26434/chemrxiv.12170424.v2 Date: 2020-04-28 Source: ChemRxiv

    The novel coronavirus SARS-CoV2, the causative agent of the worldwide pandemic disease COVID-19 MESHD, emerged in December 2019 forcing lockdown of communities in many countries. The absence of specific drugs and vaccines, the rapid transmission of the virus, and the increasing number of deaths MESHD worldwide have necessitated the need to discover substances that can be tapped for drug development. With the aid of bioinformatics and computational modelling, ninety seven secondary metabolites from fungi previously reported to exhibit antiviral properties were docked onto SARS-CoV2 enzymes involved in viral attachment, replication and post-translational mechanisms followed by in silico ADMET prediction (absorption, distribution, metabolism, excretion and toxicity MESHD) of the hit compounds. Thus, two fumiquinazoline alkaloids quinadoline B (19), scedapin C (15), and the polyketide isochaetochromin D1 (8) exhibited high binding affinities depending on the target protein. The compounds were active against the cysteine proteases, papain-like PROTEIN protease ( PLpro PROTEIN) and chymotrypsin-like protease ( 3CLpro PROTEIN) which are involved in post-translational modifications, RNA-directed RNA polymerase ( RdRp PROTEIN) which is essential in viral replication, non-structural protein 15 PROTEIN (nsp15) which is involved in evasion of host immunity, and the spike protein PROTEIN which is responsible for binding to GRP78 HGNC. Quinadoline B (19) was predicted to confer favorable ADMET values, high gastrointestinal absorptive probability and poor blood-brain barrier crossing capacities.

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins


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