TY - JOUR
T1 - Protein reliability analysis and virtual screening of natural inhibitors for SARS-CoV-2 main protease (Mpro) through docking, molecular mechanic & dynamic, and ADMET profiling
AU - Kapusta, Karina
AU - Kar, Supratik
AU - Collins, Jasmine T.
AU - Franklin, Latasha M.
AU - Kolodziejczyk, Wojciech
AU - Leszczynski, Jerzy
AU - Hill, Glake A.
N1 - Publisher Copyright:
© 2020 Informa UK Limited, trading as Taylor & Francis Group.
PY - 2021
Y1 - 2021
N2 - Due to an outbreak of COVID-19, the number of research papers devoted to in-silico drug discovery of potential antiviral drugs is increasing every day exponentially. Still, there is no specific drug to prevent or treat this novel coronavirus (SARS-CoV-2) disease. Thus, the screening for a potential remedy presents a global challenge for scientists. Up to date over a hundred crystallographic structures of SARS-CoV-2 Mpro have been deposited to Protein Data Bank. With many known proteins, the demand for a reliable target has become higher than ever, so as the choice of an efficient computational methods. Therefore, in this study comparative methods have been used for receptor-based virtual screening, targeting 9 selected structures of viral Mpro. Reliability analyses followed by re-docking of the specific co-crystallized ligand provided the best reproductivity for structures with PDB ID 6LU7, 6Y2G and 6Y2F. The influence of crystallographic water on an outcome of a virtual screening against selected targets was also investigated. Once the most reliable targets were selected, the library of easy purchasable natural compounds were retrieved from the MolPort database (10,305 compounds) and docked against the selected Mpro proteins. To ensure the efficiency of the selected compounds, binding energies for top-15 hit ligands were calculated using Molecular Mechanics as well as their absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties were predicted. Based on predicted binding energies and toxicities, top-5 compounds were selected and subjected to Molecular Dynamics simulation and found to be stable in complex to act as possible inhibitors for SARS-CoV-2. Communicated by Ramaswamy H. Sarma.
AB - Due to an outbreak of COVID-19, the number of research papers devoted to in-silico drug discovery of potential antiviral drugs is increasing every day exponentially. Still, there is no specific drug to prevent or treat this novel coronavirus (SARS-CoV-2) disease. Thus, the screening for a potential remedy presents a global challenge for scientists. Up to date over a hundred crystallographic structures of SARS-CoV-2 Mpro have been deposited to Protein Data Bank. With many known proteins, the demand for a reliable target has become higher than ever, so as the choice of an efficient computational methods. Therefore, in this study comparative methods have been used for receptor-based virtual screening, targeting 9 selected structures of viral Mpro. Reliability analyses followed by re-docking of the specific co-crystallized ligand provided the best reproductivity for structures with PDB ID 6LU7, 6Y2G and 6Y2F. The influence of crystallographic water on an outcome of a virtual screening against selected targets was also investigated. Once the most reliable targets were selected, the library of easy purchasable natural compounds were retrieved from the MolPort database (10,305 compounds) and docked against the selected Mpro proteins. To ensure the efficiency of the selected compounds, binding energies for top-15 hit ligands were calculated using Molecular Mechanics as well as their absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties were predicted. Based on predicted binding energies and toxicities, top-5 compounds were selected and subjected to Molecular Dynamics simulation and found to be stable in complex to act as possible inhibitors for SARS-CoV-2. Communicated by Ramaswamy H. Sarma.
KW - docking
KW - molecular dynamics
KW - natural compounds
KW - Protein reliability
KW - SARS-CoV-2
KW - virtual screening
UR - http://www.scopus.com/inward/record.url?scp=85089484811&partnerID=8YFLogxK
U2 - 10.1080/07391102.2020.1806930
DO - 10.1080/07391102.2020.1806930
M3 - Article
C2 - 32795148
AN - SCOPUS:85089484811
SN - 0739-1102
VL - 39
SP - 6810
EP - 6827
JO - Journal of Biomolecular Structure and Dynamics
JF - Journal of Biomolecular Structure and Dynamics
IS - 17
ER -