Structure-based virtual screening suggests inhibitors of 3-Chymotrypsin-Like Protease of SARS-CoV-2 from Vernonia amygdalina and Occinum gratissimum
| Autor: | Modupe M. Fabusiwa, Oludare M. Ogunyemi, Adegbenro P. Adegunloye, Charles O. Olaiya, Gideon A. Gyebi, Abdo A. Elfiky, Joseph O. Adebayo, Ibrahim M. Ibrahim, Joshua O. Ocheje |
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| Rok vydání: | 2021 |
| Předmět: |
Stereochemistry
medicine.medical_treatment Terpenoids Phytochemicals Health Informatics Molecular Dynamics Simulation medicine.disease_cause Antiviral Agents Article chemistry.chemical_compound Chymases medicine Humans Protease Inhibitors Coronavirus 3C Proteases Coronavirus Food herbs chemistry.chemical_classification Virtual screening Protease biology SARS-CoV-2 Molecular dynamics simulations Vernonia amygdalina Active site COVID-19 biology.organism_classification Computer Science Applications Molecular Docking Simulation Enzyme chemistry Ocimum Docking (molecular) Molecular docking biology.protein Myricetin Vernonia |
| Zdroj: | Computers in Biology and Medicine |
| DOI: | 10.21203/rs.3.rs-301445/v1 |
| Popis: | Antiviral culinary plants are potential bioresources for preventive nutraceuticals and/or antiviral drugs in COVID-19. Structure-based virtual screening was undertaken to screen 173 compounds previously reported from Vernonia amygdalina and Occinum gratissimum for direct interaction with the active site of the 3-Chymotrypsin-Like Protease (3CLpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Based on docking scores and comparison with reference inhibitors, a hit-list of 10 top phytocompounds was defined, which also had strong interactions with the catalytic centre of 3CLpro from three related strains of coronavirus (SARS-CoV, MERS-CoV, HKU4). Among these, six compounds (neoandrographolide, vernolide, isorhamnetin, chicoric acid, luteolin, and myricetin) exhibited the highest binding tendencies to the equilibrated conformers of SARS-CoV-2 3CLpro in an in-depth docking analysis to 5 different representative conformations from the cluster analysis of the molecular dynamics simulation (MDS) trajectories of the protein. In silico drug-likeness analyses revealed two drug-like terpenoids viz: neoandrographolide and vernolide as promising inhibitors of SARS-CoV-2 3CLpro. These structures were accommodated within the substrate-binding pocket; and interacted with the catalytic dyad (Cys145 and His41), the oxyanion loop (residues 138–145), and the S1/S2 sub-sites of the enzyme active site through the formation of an array of hydrogen bonds and hydrophobic interactions. Molecular dynamics simulation and binding free energy calculation revealed that the terpenoid-enzyme complexes exhibit strong interactions and structural stability. Therefore, these compounds may stabilize the conformation of the flexible oxyanion loop; and thereby interfere with the tetrahedral oxyanion intermediate formation during the proteolytic activity of the enzyme. Graphical abstract Image 1 |
| Databáze: | OpenAIRE |
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