Isatin-based virtual high throughput screening, molecular docking, DFT, QM/MM, MD and MM-PBSA study of novel inhibitors of SARS-CoV-2 main protease
| Autor: | Sethupathi Shanmugam, Venkatramanan Varadharajan, Gokulakrishnan Sivasundari Arumugam |
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| Rok vydání: | 2021 |
| Předmět: |
Isatin
2019-20 coronavirus outbreak Coronavirus disease 2019 (COVID-19) Adipates medicine.medical_treatment Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) High-throughput screening Molecular Dynamics Simulation Ligands medicine.disease_cause QM/MM chemistry.chemical_compound Structural Biology medicine Humans Protease Inhibitors Molecular Biology Coronavirus 3C Proteases Coronavirus Protease SARS-CoV-2 Succinates General Medicine Virology High-Throughput Screening Assays COVID-19 Drug Treatment Molecular Docking Simulation Zinc chemistry |
| DOI: | 10.6084/m9.figshare.14306838.v1 |
| Popis: | Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a rapidly growing health care emergency across the world. One of the viral proteases called main protease or Mpro, plays a crucial role in the replication of SARS-CoV-2. As the structure of Mpro of SARS-CoV-2 is similar to the Mpro of SARS-CoV-1 (responsible for SARS outbreak between 2002 and 2004), we hypothesize that the inhibitors of SARS-CoV-1 Mpro can also inhibit the Mpro of SARS-CoV-2. To test this hypothesis, a total of 79 isatin derivatives, which inhibited Mpro activity under in vitro conditions, were selected from the literature, and then screened through AutoDock Vina. The chemical features of the top 5 isatin derivatives with low binding energies (−8.5 to −8.2 kcal/mol) were used to screen similar types of compounds from several small-molecule libraries containing 15856508 compounds. A total of 1,609 compounds with similarity score ≥ 6 were screened and then subjected to docking as well as ADME analysis. Among the compounds screened, 4 ligands form Zinc drug-like library (ZINC000008848565, ZINC000009513563, ZINC000036759789 and ZINC000046053855) showed good ADMET properties, low binding energy (−8.4 to −8.6 kcal/mol), low interaction energy (−72.62 to −50.01 kcal/mol) and high structural stability with Mpro. Hence, the selected ligands might serve as the lead candidates for further wet laboratory validation, optimization and development. Communicated by Ramaswamy H. Sarma |
| Databáze: | OpenAIRE |
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