In silico exploration of novel protease inhibitors against coronavirus 2019 (COVID-19)
| Autor: | Marzieh Ghodrati, Jahan B. Ghasemi, Elham Aghaee |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Virtual screening In silico medicine.medical_treatment Computer applications to medicine. Medical informatics R858-859.7 Health Informatics Computational biology Article 03 medical and health sciences ADME studies 0302 clinical medicine Molecular dynamics simulation medicine ADME Protease Drug discovery Chemistry COVID-19 Lopinavir 030104 developmental biology Nelfinavir 030220 oncology & carcinogenesis Main protease Molecular docking Ritonavir medicine.drug |
| Zdroj: | Informatics in Medicine Unlocked, Vol 23, Iss, Pp 100516-(2021) Informatics in Medicine Unlocked |
| ISSN: | 2352-9148 |
| Popis: | The spread of SARS-CoV-2 has affected human health globally. Hence, it is necessary to rapidly find the drug-candidates that can be used to treat the infection. Since the main protease (Mpro) is the key protein in the virus's life cycle, Mpro is served as one of the critical targets of antiviral treatment. We employed virtual screening tools to search for new inhibitors to accelerate the drug discovery process. The hit compounds were subsequently docked into the active site of SARS-CoV-2 main protease and ranked by their binding energy. Furthermore, in-silico ADME studies were performed to probe for adoption with the standard ranges. Finally, molecular dynamics simulations were applied to study the protein-drug complex's fluctuation over time in an aqueous medium. This study indicates that the interaction energy of the top ten retrieved compounds with COVID-19 main protease is much higher than the interaction energy of some currently in use protease drugs such as ML188, nelfinavir, lopinavir, ritonavir, and α-ketoamide. Among the discovered compounds, Pubchem44326934 showed druglike properties and was further analyzed by MD and MM/PBSA approaches. Besides, the constant binding free energy over MD trajectories suggests a probable drug possessing antiviral properties. MD simulations demonstrate that GLU166 and GLN189 are the most important residues of Mpro, which interact with inhibitors. Graphical abstract Image 1 Highlights • Novel COVID-19 Mpro inhibitors were found from theoretical studies. • The proposed compounds show much better interaction energy with Mpro than some currently in use protease drugs. • GLU166 and GLN189 are the principal amino acids involved in the interaction. |
| Databáze: | OpenAIRE |
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