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  1. Article ; Online: The Dual-Targeted Fusion Inhibitor Clofazimine Binds to the S2 Segment of the SARS-CoV-2 Spike Protein.

    Freidel, Matthew R / Vakhariya, Pratiti A / Sardarni, Shalinder K / Armen, Roger S

    Viruses

    2024  Volume 16, Issue 4

    Abstract: Clofazimine and Arbidol have both been reported to be effective in vitro SARS-CoV-2 fusion inhibitors. Both are promising drugs that have been repurposed for the treatment of COVID-19 and have been used in several previous and ongoing clinical trials. ... ...

    Abstract Clofazimine and Arbidol have both been reported to be effective in vitro SARS-CoV-2 fusion inhibitors. Both are promising drugs that have been repurposed for the treatment of COVID-19 and have been used in several previous and ongoing clinical trials. Small-molecule bindings to expressed constructs of the trimeric S2 segment of Spike and the full-length SARS-CoV-2 Spike protein were measured using a Surface Plasmon Resonance (SPR) binding assay. We demonstrate that Clofazimine, Toremifene, Arbidol and its derivatives bind to the S2 segment of the Spike protein. Clofazimine provided the most reliable and highest-quality SPR data for binding with S2 over the conditions explored. A molecular docking approach was used to identify the most favorable binding sites on the S2 segment in the prefusion conformation, highlighting two possible small-molecule binding sites for fusion inhibitors. Results related to molecular docking and modeling of the structure-activity relationship (SAR) of a newly reported series of Clofazimine derivatives support the proposed Clofazimine binding site on the S2 segment. When the proposed Clofazimine binding site is superimposed with other experimentally determined coronavirus structures in structure-sequence alignments, the changes in sequence and structure may rationalize the broad-spectrum antiviral activity of Clofazimine in closely related coronaviruses such as SARS-CoV, MERS, hCoV-229E, and hCoV-OC43.
    MeSH term(s) Spike Glycoprotein, Coronavirus/metabolism ; Spike Glycoprotein, Coronavirus/chemistry ; Spike Glycoprotein, Coronavirus/antagonists & inhibitors ; Clofazimine/pharmacology ; Clofazimine/chemistry ; Clofazimine/metabolism ; Molecular Docking Simulation ; SARS-CoV-2/drug effects ; Humans ; Binding Sites ; Protein Binding ; Antiviral Agents/pharmacology ; Antiviral Agents/chemistry ; COVID-19 Drug Treatment ; Structure-Activity Relationship ; Surface Plasmon Resonance ; Viral Fusion Protein Inhibitors/pharmacology ; Viral Fusion Protein Inhibitors/chemistry ; Indoles ; Sulfides
    Chemical Substances Spike Glycoprotein, Coronavirus ; Clofazimine (D959AE5USF) ; spike protein, SARS-CoV-2 ; Antiviral Agents ; Viral Fusion Protein Inhibitors ; umifenovir (93M09WW4RU) ; Indoles ; Sulfides
    Language English
    Publishing date 2024-04-20
    Publishing country Switzerland
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2516098-9
    ISSN 1999-4915 ; 1999-4915
    ISSN (online) 1999-4915
    ISSN 1999-4915
    DOI 10.3390/v16040640
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Modeling the Structure-Activity Relationship of Arbidol Derivatives and Other SARS-CoV-2 Fusion Inhibitors Targeting the S2 Segment of the Spike Protein.

    Freidel, Matthew R / Armen, Roger S

    Journal of chemical information and modeling

    2021  Volume 61, Issue 12, Page(s) 5906–5922

    Abstract: Umifenovir (Arbidol) has been reported to exhibit some degree of efficacy in multiple clinical trials for the treatment of COVID-19 as a monotherapy. It has also demonstrated synergistic inhibition of SARS-CoV-2 with other direct-acting antivirals such ... ...

    Abstract Umifenovir (Arbidol) has been reported to exhibit some degree of efficacy in multiple clinical trials for the treatment of COVID-19 as a monotherapy. It has also demonstrated synergistic inhibition of SARS-CoV-2 with other direct-acting antivirals such as Remdesivir. A computational approach was used to identify the most favorable binding site to the SARS-CoV-2 Spike S2 segment and to perform virtual screening. Compounds selected from modeling were evaluated in a live SARS-CoV-2 infection assay. An Arbidol (ARB) derivative with substitutions at both the C-4 and C-6 positions was found to exhibit a modest improvement in activity and solubility properties in comparison to ARB. However, all of the derivatives were found to only be partial inhibitors, rather than full inhibitors in a virus-induced cytopathic effect-based assay. The binding mode is also corroborated by parallel modeling of a series of oleanolic acid trisaccharide saponin fusion inhibitors shown to bind to the S2 segment. Recently determined experimental structures of the Spike protein allowed atomic resolution modeling of fusion inhibitor binding as a function of pH, and the implications for the molecular mechanism of direct-acting fusion inhibitors targeting the S2 segment are discussed.
    MeSH term(s) Angiotensin Receptor Antagonists ; Angiotensin-Converting Enzyme Inhibitors ; Antiviral Agents/pharmacology ; COVID-19 ; Hepatitis C, Chronic ; Humans ; Indoles ; SARS-CoV-2 ; Spike Glycoprotein, Coronavirus ; Structure-Activity Relationship ; Virus Internalization
    Chemical Substances Angiotensin Receptor Antagonists ; Angiotensin-Converting Enzyme Inhibitors ; Antiviral Agents ; Indoles ; Spike Glycoprotein, Coronavirus ; umifenovir (93M09WW4RU)
    Language English
    Publishing date 2021-12-13
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 190019-5
    ISSN 1549-960X ; 0095-2338
    ISSN (online) 1549-960X
    ISSN 0095-2338
    DOI 10.1021/acs.jcim.1c01061
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Mapping major SARS-CoV-2 drug targets and assessment of druggability using computational fragment screening: Identification of an allosteric small-molecule binding site on the Nsp13 helicase.

    Freidel, Matthew R / Armen, Roger S

    PloS one

    2021  Volume 16, Issue 2, Page(s) e0246181

    Abstract: The 2019 emergence of, SARS-CoV-2 has tragically taken an immense toll on human life and far reaching impacts on society. There is a need to identify effective antivirals with diverse mechanisms of action in order to accelerate preclinical development. ... ...

    Abstract The 2019 emergence of, SARS-CoV-2 has tragically taken an immense toll on human life and far reaching impacts on society. There is a need to identify effective antivirals with diverse mechanisms of action in order to accelerate preclinical development. This study focused on five of the most established drug target proteins for direct acting small molecule antivirals: Nsp5 Main Protease, Nsp12 RNA-dependent RNA polymerase, Nsp13 Helicase, Nsp16 2'-O methyltransferase and the S2 subunit of the Spike protein. A workflow of solvent mapping and free energy calculations was used to identify and characterize favorable small-molecule binding sites for an aromatic pharmacophore (benzene). After identifying the most favorable sites, calculated ligand efficiencies were compared utilizing computational fragment screening. The most favorable sites overall were located on Nsp12 and Nsp16, whereas the most favorable sites for Nsp13 and S2 Spike had comparatively lower ligand efficiencies relative to Nsp12 and Nsp16. Utilizing fragment screening on numerous possible sites on Nsp13 helicase, we identified a favorable allosteric site on the N-terminal zinc binding domain (ZBD) that may be amenable to virtual or biophysical fragment screening efforts. Recent structural studies of the Nsp12:Nsp13 replication-transcription complex experimentally corroborates ligand binding at this site, which is revealed to be a functional Nsp8:Nsp13 protein-protein interaction site in the complex. Detailed structural analysis of Nsp13 ZBD conformations show the role of induced-fit flexibility in this ligand binding site and identify which conformational states are associated with efficient ligand binding. We hope that this map of over 200 possible small-molecule binding sites for these drug targets may be of use for ongoing discovery, design, and drug repurposing efforts. This information may be used to prioritize screening efforts or aid in the process of deciphering how a screening hit may bind to a specific target protein.
    MeSH term(s) Allosteric Site ; Antiviral Agents/pharmacology ; Binding Sites ; COVID-19/drug therapy ; COVID-19/metabolism ; COVID-19/virology ; Computational Biology/methods ; Coronavirus 3C Proteases/antagonists & inhibitors ; Coronavirus 3C Proteases/chemistry ; Coronavirus 3C Proteases/metabolism ; Coronavirus RNA-Dependent RNA Polymerase/antagonists & inhibitors ; Coronavirus RNA-Dependent RNA Polymerase/chemistry ; Coronavirus RNA-Dependent RNA Polymerase/metabolism ; Humans ; Methyltransferases/antagonists & inhibitors ; Methyltransferases/chemistry ; Methyltransferases/metabolism ; Models, Molecular ; Molecular Targeted Therapy ; Protein Binding ; RNA Helicases/antagonists & inhibitors ; RNA Helicases/chemistry ; RNA Helicases/metabolism ; RNA-Dependent RNA Polymerase/metabolism ; SARS-CoV-2/drug effects ; SARS-CoV-2/metabolism ; Viral Nonstructural Proteins/antagonists & inhibitors ; Viral Nonstructural Proteins/chemistry ; Viral Nonstructural Proteins/metabolism ; Virus Replication/drug effects
    Chemical Substances Antiviral Agents ; NSP16 protein, SARS-CoV-2 ; Viral Nonstructural Proteins ; Methyltransferases (EC 2.1.1.-) ; Nsp13 protein, SARS-CoV (EC 2.1.1.-) ; Coronavirus RNA-Dependent RNA Polymerase (EC 2.7.7.48) ; NSP12 protein, SARS-CoV-2 (EC 2.7.7.48) ; RNA-Dependent RNA Polymerase (EC 2.7.7.48) ; 3C-like protease, SARS coronavirus (EC 3.4.22.-) ; Coronavirus 3C Proteases (EC 3.4.22.28) ; RNA Helicases (EC 3.6.4.13)
    Language English
    Publishing date 2021-02-17
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ISSN 1932-6203
    ISSN (online) 1932-6203
    DOI 10.1371/journal.pone.0246181
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Mapping major SARS-CoV-2 drug targets and assessment of druggability using computational fragment screening

    Matthew R Freidel / Roger S Armen

    PLoS ONE, Vol 16, Iss 2, p e

    Identification of an allosteric small-molecule binding site on the Nsp13 helicase.

    2021  Volume 0246181

    Abstract: The 2019 emergence of, SARS-CoV-2 has tragically taken an immense toll on human life and far reaching impacts on society. There is a need to identify effective antivirals with diverse mechanisms of action in order to accelerate preclinical development. ... ...

    Abstract The 2019 emergence of, SARS-CoV-2 has tragically taken an immense toll on human life and far reaching impacts on society. There is a need to identify effective antivirals with diverse mechanisms of action in order to accelerate preclinical development. This study focused on five of the most established drug target proteins for direct acting small molecule antivirals: Nsp5 Main Protease, Nsp12 RNA-dependent RNA polymerase, Nsp13 Helicase, Nsp16 2'-O methyltransferase and the S2 subunit of the Spike protein. A workflow of solvent mapping and free energy calculations was used to identify and characterize favorable small-molecule binding sites for an aromatic pharmacophore (benzene). After identifying the most favorable sites, calculated ligand efficiencies were compared utilizing computational fragment screening. The most favorable sites overall were located on Nsp12 and Nsp16, whereas the most favorable sites for Nsp13 and S2 Spike had comparatively lower ligand efficiencies relative to Nsp12 and Nsp16. Utilizing fragment screening on numerous possible sites on Nsp13 helicase, we identified a favorable allosteric site on the N-terminal zinc binding domain (ZBD) that may be amenable to virtual or biophysical fragment screening efforts. Recent structural studies of the Nsp12:Nsp13 replication-transcription complex experimentally corroborates ligand binding at this site, which is revealed to be a functional Nsp8:Nsp13 protein-protein interaction site in the complex. Detailed structural analysis of Nsp13 ZBD conformations show the role of induced-fit flexibility in this ligand binding site and identify which conformational states are associated with efficient ligand binding. We hope that this map of over 200 possible small-molecule binding sites for these drug targets may be of use for ongoing discovery, design, and drug repurposing efforts. This information may be used to prioritize screening efforts or aid in the process of deciphering how a screening hit may bind to a specific target protein.
    Keywords Medicine ; R ; Science ; Q
    Subject code 500
    Language English
    Publishing date 2021-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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