Protein reliability analysis and virtual screening of natural inhibitors for SARS-CoV-2 main protease (Mpro) through docking, molecular mechanic & dynamic, and ADMET profiling
| Autor: | Glake Hill, Wojciech Kolodziejczyk, Jasmine T. Collins, Supratik Kar, Jerzy Leszczynski, Karina Kapusta, Latasha M. Franklin |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
Protein Data Bank (RCSB PDB) Protein reliability Computational biology Molecular Dynamics Simulation medicine.disease_cause Molecular mechanics Structural Biology natural compounds medicine Humans Protease Inhibitors Molecular Biology Coronavirus Virtual screening Chemistry Drug discovery SARS-CoV-2 COVID-19 Reproducibility of Results computer.file_format General Medicine virtual screening Protein Data Bank molecular dynamics Molecular Docking Simulation Docking (molecular) docking computer Research Article Peptide Hydrolases |
| Zdroj: | Journal of Biomolecular Structure and Dynamics Journal of Biomolecular Structure & Dynamics article-version (VoR) Version of Record |
| ISSN: | 1538-0254 0739-1102 |
| DOI: | 10.1080/07391102.2020.1806930 |
| Popis: | 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 |
| Databáze: | OpenAIRE |
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