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  1. Article ; Online: Establishing an Analogue Based In Silico Pipeline in the Pursuit of Novel Inhibitory Scaffolds against the SARS Coronavirus 2 Papain-Like Protease.

    Hajbabaie, Roxanna / Harper, Matthew T / Rahman, Taufiq

    Molecules (Basel, Switzerland)

    2021  Volume 26, Issue 4

    Abstract: The ongoing coronavirus pandemic has been a burden on the worldwide population, with mass fatalities and devastating socioeconomic consequences. It has particularly drawn attention to the lack of approved small-molecule drugs to inhibit SARS ... ...

    Abstract The ongoing coronavirus pandemic has been a burden on the worldwide population, with mass fatalities and devastating socioeconomic consequences. It has particularly drawn attention to the lack of approved small-molecule drugs to inhibit SARS coronaviruses. Importantly, lessons learned from the SARS outbreak of 2002-2004, caused by severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1), can be applied to current drug discovery ventures. SARS-CoV-1 and SARS-CoV-2 both possess two cysteine proteases, the main protease (M
    MeSH term(s) Antiviral Agents/chemistry ; Antiviral Agents/therapeutic use ; COVID-19/enzymology ; Coronavirus 3C Proteases/antagonists & inhibitors ; Coronavirus 3C Proteases/chemistry ; Crystallography, X-Ray ; Cysteine Proteinase Inhibitors/chemistry ; Cysteine Proteinase Inhibitors/therapeutic use ; Drug Evaluation, Preclinical ; Humans ; Molecular Docking Simulation ; SARS-CoV-2/enzymology ; COVID-19 Drug Treatment
    Chemical Substances Antiviral Agents ; Cysteine Proteinase Inhibitors ; 3C-like proteinase, SARS-CoV-2 (EC 3.4.22.-) ; Coronavirus 3C Proteases (EC 3.4.22.28)
    Language English
    Publishing date 2021-02-20
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 1413402-0
    ISSN 1420-3049 ; 1431-5165 ; 1420-3049
    ISSN (online) 1420-3049
    ISSN 1431-5165 ; 1420-3049
    DOI 10.3390/molecules26041134
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.MO 81: Show issues

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  2. Article ; Online: Establishing an Analogue Based In Silico Pipeline in the Pursuit of Novel Inhibitory Scaffolds against the SARS Coronavirus 2 Papain-Like Protease

    Roxanna Hajbabaie / Matthew T. Harper / Taufiq Rahman

    Molecules, Vol 26, Iss 4, p

    2021  Volume 1134

    Abstract: The ongoing coronavirus pandemic has been a burden on the worldwide population, with mass fatalities and devastating socioeconomic consequences. It has particularly drawn attention to the lack of approved small-molecule drugs to inhibit SARS ... ...

    Abstract The ongoing coronavirus pandemic has been a burden on the worldwide population, with mass fatalities and devastating socioeconomic consequences. It has particularly drawn attention to the lack of approved small-molecule drugs to inhibit SARS coronaviruses. Importantly, lessons learned from the SARS outbreak of 2002–2004, caused by severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1), can be applied to current drug discovery ventures. SARS-CoV-1 and SARS-CoV-2 both possess two cysteine proteases, the main protease (M pro ) and the papain-like protease (PL pro ), which play a significant role in facilitating viral replication, and are important drug targets. The non-covalent inhibitor, GRL-0617, which was found to inhibit replication of SARS-CoV-1, and more recently SARS-CoV-2, is the only PL pro inhibitor co-crystallised with the recently solved SARS-CoV-2 PL pro crystal structure. Therefore, the GRL-0617 structural template and pharmacophore features are instrumental in the design and development of more potent PL pro inhibitors. In this work, we conducted scaffold hopping using GRL-0617 as a reference to screen over 339,000 ligands in the chemical space using the ChemDiv, MayBridge, and Enamine screening libraries. Twenty-four distinct scaffolds with structural and electrostatic similarity to GRL-0617 were obtained. These proceeded to molecular docking against PL pro using the AutoDock tools. Of two compounds that showed the most favourable predicted binding affinities to the target site, as well as comparable protein-ligand interactions to GRL-0617, one was chosen for further analogue-based work. Twenty-seven analogues of this compound were further docked against the PL pro , which resulted in two additional hits with promising docking profiles. Our in silico pipeline consisted of an integrative four-step approach: (1) ligand-based virtual screening (scaffold-hopping), (2) molecular docking, (3) an analogue search, and, (4) evaluation of scaffold drug-likeness, to identify promising scaffolds and ...
    Keywords drug discovery ; papain-like protease ; PL pro ; SARS coronavirus 2 ; COVID-19 ; analogues ; Organic chemistry ; QD241-441
    Subject code 333
    Language English
    Publishing date 2021-02-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Novel Small-Molecule Scaffolds as Candidates against the SARS Coronavirus 2 Main Protease: A Fragment-Guided in Silico Approach.

    Augustin, Teresa L / Hajbabaie, Roxanna / Harper, Matthew T / Rahman, Taufiq

    Molecules (Basel, Switzerland)

    2020  Volume 25, Issue 23

    Abstract: The ongoing pandemic caused by the novel coronavirus has been the greatest global health crisis since the Spanish flu pandemic of 1918. Thus far, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in over 1 million deaths, and ... ...

    Abstract The ongoing pandemic caused by the novel coronavirus has been the greatest global health crisis since the Spanish flu pandemic of 1918. Thus far, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in over 1 million deaths, and there is no cure or vaccine to date. The recently solved crystal structure of the SARS-CoV-2 main protease has been a major focus for drug-discovery efforts. Here, we present a fragment-guided approach using ZINCPharmer, where 17 active fragments known to bind to the catalytic centre of the SARS-CoV-2 main protease (SARS-CoV-2 M
    MeSH term(s) COVID-19/drug therapy ; COVID-19/virology ; Coronavirus 3C Proteases/antagonists & inhibitors ; Coronavirus 3C Proteases/chemistry ; Humans ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; Pandemics ; SARS-CoV-2/chemistry ; SARS-CoV-2/drug effects ; SARS-CoV-2/pathogenicity
    Chemical Substances 3C-like proteinase, SARS-CoV-2 (EC 3.4.22.-) ; Coronavirus 3C Proteases (EC 3.4.22.28)
    Language English
    Publishing date 2020-11-24
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 1413402-0
    ISSN 1420-3049 ; 1431-5165 ; 1420-3049
    ISSN (online) 1420-3049
    ISSN 1431-5165 ; 1420-3049
    DOI 10.3390/molecules25235501
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.MO 81: Show issues

    Order via subito

    This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

  4. Article ; Online: Novel Small Molecule Scaffolds as Candidates Against the SARS Coronavirus 2 Main Protease

    Harper, Matthew / Rahman, Taufiq / Augustin, Teresa / Hajbabaie, Roxanna

    a Fragment-Guided In Silico Approach

    2020  

    Abstract: The ongoing pandemic caused by the novel coronavirus has been the biggest worldwide health crisis since the Spanish Flu pandemic of 1918. Thus far, the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has resulted in over one million deaths, ... ...

    Abstract The ongoing pandemic caused by the novel coronavirus has been the biggest worldwide health crisis since the Spanish Flu pandemic of 1918. Thus far, the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has resulted in over one million deaths, and there is no cure or a vaccine to date. The recently solved crystal structure of the SARS-CoV-2 main protease has been a major focus for drug discovery efforts. Here, we present a fragment-guided approach using ZINCPharmer, where 17 active fragments known to bind to the catalytic center of the SARS-CoV-2 main protease (SARS-CoV-2 Mpro) were used as the pharmacophore queries to search the ZINC databases of natural compounds and natural derivatives. This search yielded 134 hits that were then subjected to multiple rounds of in silico analyses, including blind and focused docking against the 3D structure of the main protease. We scrutinized the poses, scores, and protein-ligand interactions of 15 hits and selected seven. The scaffolds of the seven hits were structurally distinct from the known inhibitor scaffolds, thus indicating scaffold novelty. Herein, our work presents several novel scaffolds as potential candidates for experimental validation against the SARS-CoV-2 Mpro.
    Keywords covid19
    Publishing date 2020-11-19T00:30:36Z
    Publisher MDPI AG
    Publishing country uk
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

    Full text online

    More links

    Kategorien

    Inter-library loan at ZB MED

    Your chosen title can be delivered directly to ZB MED Cologne location if you are registered as a user at ZB MED Cologne.

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