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  1. Article ; Online: Molecular dynamics and in silico mutagenesis on the reversible inhibitor-bound SARS-CoV-2 main protease complexes reveal the role of lateral pocket in enhancing the ligand affinity.

    Weng, Ying Li / Naik, Shiv Rakesh / Dingelstad, Nadia / Lugo, Miguel R / Kalyaanamoorthy, Subha / Ganesan, Aravindhan

    Scientific reports

    2021  Volume 11, Issue 1, Page(s) 7429

    Abstract: The 2019 novel coronavirus pandemic caused by SARS-CoV-2 remains a serious health threat to humans and there is an urgent need to develop therapeutics against this deadly virus. Recent scientific evidences have suggested that the main protease ( ... ...

    Abstract The 2019 novel coronavirus pandemic caused by SARS-CoV-2 remains a serious health threat to humans and there is an urgent need to develop therapeutics against this deadly virus. Recent scientific evidences have suggested that the main protease (M
    MeSH term(s) Binding Sites ; COVID-19/pathology ; COVID-19/virology ; Catalytic Domain ; Databases, Protein ; Humans ; Ligands ; Molecular Dynamics Simulation ; Mutagenesis, Site-Directed ; Principal Component Analysis ; Protease Inhibitors/chemistry ; Protease Inhibitors/metabolism ; SARS-CoV-2/isolation & purification ; SARS-CoV-2/metabolism ; Thermodynamics ; Viral Matrix Proteins/antagonists & inhibitors ; Viral Matrix Proteins/metabolism
    Chemical Substances Ligands ; Protease Inhibitors ; Viral Matrix Proteins ; membrane protein, SARS-CoV-2
    Language English
    Publishing date 2021-04-01
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-021-86471-0
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Structure-based virtual screening, molecular dynamics and binding affinity calculations of some potential phytocompounds against SARS-CoV-2.

    Naik, Shiv Rakesh / Bharadwaj, Prashant / Dingelstad, Nadia / Kalyaanamoorthy, Subha / Mandal, Subhash C / Ganesan, Aravindhan / Chattopadhyay, Debprasad / Palit, Partha

    Journal of biomolecular structure & dynamics

    2021  Volume 40, Issue 15, Page(s) 6921–6938

    Abstract: COVID-19 caused by a positive-sense single stranded RNA virus named as severe acute respiratory syndrome-Coronavirus-2 (SARS-CoV-2) triggered the global pandemic. This virus has infected about 10.37 Crores and taken lives of 2.24 Crores people of 213 ... ...

    Abstract COVID-19 caused by a positive-sense single stranded RNA virus named as severe acute respiratory syndrome-Coronavirus-2 (SARS-CoV-2) triggered the global pandemic. This virus has infected about 10.37 Crores and taken lives of 2.24 Crores people of 213 countries to date. To cope-up this emergency clinical trials are undergoing with some existing drugs like remdesivir, flavipiravir, lopinavir-ritonavir, nafamostat, doxycycline, hydroxy-chloroquine, dexamethasone, etc., despite their severe toxicity and health hazards among diabetics, hypertensive, cardiac patients or normal individuals. The lack of safe and approved treatment for COVID-19 has forced the scientific community to find novel and safe compounds with potential efficacy. This study evaluates a few selective herbal compounds like glucoraphanin, vitexin, niazinin, etc., as a potential inhibitor of the spike protein and 3-chymotrypsin-like protease (3CLpro) or main protease (Mpro) of SARS-COV-2 through
    MeSH term(s) COVID-19/drug therapy ; Coronavirus 3C Proteases ; Cysteine Endopeptidases/chemistry ; Humans ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; Protease Inhibitors ; SARS-CoV-2
    Chemical Substances Protease Inhibitors ; Cysteine Endopeptidases (EC 3.4.22.-) ; Coronavirus 3C Proteases (EC 3.4.22.28)
    Language English
    Publishing date 2021-03-08
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 49157-3
    ISSN 1538-0254 ; 0739-1102
    ISSN (online) 1538-0254
    ISSN 0739-1102
    DOI 10.1080/07391102.2021.1891969
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Molecular dynamics and in silico mutagenesis on the reversible inhibitor-bound SARS-CoV-2 main protease complexes reveal the role of lateral pocket in enhancing the ligand affinity

    Ying Li Weng / Shiv Rakesh Naik / Nadia Dingelstad / Miguel R. Lugo / Subha Kalyaanamoorthy / Aravindhan Ganesan

    Scientific Reports, Vol 11, Iss 1, Pp 1-

    2021  Volume 22

    Abstract: Abstract The 2019 novel coronavirus pandemic caused by SARS-CoV-2 remains a serious health threat to humans and there is an urgent need to develop therapeutics against this deadly virus. Recent scientific evidences have suggested that the main protease ( ... ...

    Abstract Abstract The 2019 novel coronavirus pandemic caused by SARS-CoV-2 remains a serious health threat to humans and there is an urgent need to develop therapeutics against this deadly virus. Recent scientific evidences have suggested that the main protease (Mpro) enzyme in SARS-CoV-2 can be an ideal drug target due to its crucial role in the viral replication and transcription processes. Therefore, there are ongoing research efforts to identify drug candidates against SARS-CoV-2 Mpro that resulted in hundreds of X-ray crystal structures of ligand-bound Mpro complexes in the Protein Data Bank (PDB) describing the interactions of different fragment chemotypes within different sites of the Mpro. In this work, we performed rigorous molecular dynamics (MD) simulation of 62 reversible ligand–Mpro complexes in the PDB to gain mechanistic insights about their interactions at the atomic level. Using a total of over 3 µs long MD trajectories, we characterized different pockets in the apo Mpro structure, and analyzed the dynamic interactions and binding affinity of ligands within those pockets. Our results identified the key residues that stabilize the ligands in the catalytic sites and other pockets of Mpro. Our analyses unraveled the role of a lateral pocket in the catalytic site in Mpro that is critical for enhancing the ligand binding to the enzyme. We also highlighted the important contribution from HIS163 in the lateral pocket towards ligand binding and affinity against Mpro through computational mutation analyses. Further, we revealed the effects of explicit water molecules and Mpro dimerization in the ligand association with the target. Thus, comprehensive molecular-level insights gained from this work can be useful to identify or design potent small molecule inhibitors against SARS-CoV-2 Mpro.
    Keywords Medicine ; R ; Science ; Q
    Subject code 540
    Language English
    Publishing date 2021-04-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Molecular dynamics and in silico mutagenesis on the reversible inhibitor-bound SARS-CoV-2 Main Protease complexes reveal the role of a lateral pocket in enhancing the ligand affinity

    Li Weng, Ying / Naik, Shiv Rakesh / Dingelstad, Nadia / Kalyaanamoorthy, Subha / Ganesan, Aravindhan

    bioRxiv

    Abstract: The 2019 novel coronavirus pandemic caused by SARS-CoV-2 remains a serious health threat to humans and a number of countries are already in the middle of the second wave of infection. There is an urgent need to develop therapeutics against this deadly ... ...

    Abstract The 2019 novel coronavirus pandemic caused by SARS-CoV-2 remains a serious health threat to humans and a number of countries are already in the middle of the second wave of infection. There is an urgent need to develop therapeutics against this deadly virus. Recent scientific evidences have suggested that the main protease (Mpro) enzyme in SARS-CoV-2 can be an ideal drug target due to its crucial role in the viral replication and transcription processes. Therefore, there are ongoing research efforts to identify drug candidates against SARS-CoV-2 Mpro that resulted in hundreds of X-ray crystal structures of ligand bound Mpro complexes in the protein data bank (PDB) that describe structural details of different chemotypes of fragments binding within different sites in Mpro. In this work, we perform rigorous molecular dynamics (MD) simulation of 62 reversible ligand-Mpro complexes in the PDB to gain mechanistic insights about their interactions at atomic level. Using a total of ~2.25 μs long MD trajectories, we identified and characterized different pockets and their conformational dynamics in the apo Mpro structure. Later, using the published PDB structures, we analyzed the dynamic interactions and binding affinity of small ligands within those pockets. Our results identified the key residues that stabilize the ligands in the catalytic sites and other pockets in Mpro. Our analyses unraveled the role of a lateral pocket in the catalytic site in Mpro that is critical for enhancing the ligand binding to the enzyme. We also highlighted the important contribution from HIS163 in this lateral pocket towards ligand binding and affinity against Mpro through computational mutation analyses. Further, we revealed the effects of explicit water molecules and Mpro dimerization in the ligand association with the target. Thus, comprehensive molecular level insights gained from this work can be useful to identify or design potent small molecule inhibitors against SARS-CoV-2 Mpro.
    Keywords covid19
    Publisher BioRxiv; WHO
    Document type Article ; Online
    DOI 10.1101/2020.10.31.363309
    Database COVID19

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  5. Article ; Online: Molecular dynamics and in silico mutagenesis on the reversible inhibitor-bound SARS-CoV-2 Main Protease complexes reveal the role of lateral pocket in enhancing the ligand affinity

    Weng, Ying Li / Naik, Shiv Rakesh / Dingelstad, Nadia / Kalyaanamoorthy, Subha / Ganesan, Aravindhan

    bioRxiv

    Abstract: The 2019 novel coronavirus pandemic caused by SARS-CoV-2 remains a serious health threat to humans and a number of countries are already in the middle of the second wave of infection. There is an urgent need to develop therapeutics against this deadly ... ...

    Abstract The 2019 novel coronavirus pandemic caused by SARS-CoV-2 remains a serious health threat to humans and a number of countries are already in the middle of the second wave of infection. There is an urgent need to develop therapeutics against this deadly virus. Recent scientific evidences have suggested that the main protease (Mpro) enzyme in SARS-CoV-2 can be an ideal drug target due to its crucial role in the viral replication and transcription processes. Therefore, there are ongoing research efforts to identify drug candidates against SARS-CoV-2 Mpro that resulted in hundreds of X-ray crystal structures of ligand bound Mpro complexes in the protein data bank (PDB) that describe structural details of different chemotypes of fragments binding within different sites in Mpro. In this work, we perform rigorous molecular dynamics (MD) simulation of 62 reversible ligand-Mpro complexes in the PDB to gain mechanistic insights about their interactions at atomic level. Using a total of ~2.25 microseconds long MD trajectories, we identified and characterized different pockets and their conformational dynamics in the apo Mpro structure. Later, using the published PDB structures, we analyzed the dynamic interactions and binding affinity of small ligands within those pockets. Our results identified the key residues that stabilize the ligands in the catalytic sites and other pockets in Mpro. Our analyses unraveled the role of a lateral pocket in the catalytic site in Mpro that is critical for enhancing the ligand binding to the enzyme. We also highlighted the important contribution from HIS163 in this lateral pocket towards ligand binding and affinity against Mpro through computational mutation analyses. Further, we revealed the effects of explicit water molecules and Mpro dimerization in the ligand association with the target. Thus, comprehensive molecular level insights gained from this work can be useful to identify or design potent small molecule inhibitors against SARS-CoV-2 Mpro.
    Keywords covid19
    Language English
    Publishing date 2020-11-01
    Publisher Cold Spring Harbor Laboratory
    Document type Article ; Online
    DOI 10.1101/2020.10.31.363309
    Database COVID19

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    Inter-library loan at ZB MED

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