Virtual Screening and Quantum Chemistry Analysis for SARS-CoV-2 RNA-Dependent RNA Polymerase Using the ChEMBL Database: Reproduction of the Remdesivir-RTP and Favipiravir-RTP Binding Modes Obtained from Cryo-EM Experiments with High Binding Affinity
| Autor: | Motonori Tsuji |
|---|---|
| Rok vydání: | 2022 |
| Předmět: |
Alanine
SARS-CoV-2 Reproduction Cryoelectron Microscopy Organic Chemistry Nucleosides General Medicine RNA-Dependent RNA Polymerase Amides Antiviral Agents COVID-19 RNA-dependent RNA polymerase virtual screening quantum chemistry calculation drug repositioning ONIOM geometry optimization calculation frequency analysis fragment molecular orbital calculation Adenosine Monophosphate Catalysis COVID-19 Drug Treatment Computer Science Applications Molecular Docking Simulation Inorganic Chemistry Polyphosphates Pyrazines Humans RNA Viral Ribonucleosides Physical and Theoretical Chemistry Molecular Biology Spectroscopy |
| Zdroj: | International Journal of Molecular Sciences; Volume 23; Issue 19; Pages: 11009 |
| ISSN: | 1422-0067 |
| Popis: | The novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was identified as the pathogenic cause of coronavirus disease 2019 (COVID-19). The RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 is a potential target for the treatment of COVID-19. An RdRp complex:dsRNA structure suitable for docking simulations was prepared using a cryo-electron microscopy (cryo-EM) structure (PDB ID: 7AAP; resolution, 2.60 Å) that was reported recently. Structural refinement was performed using energy calculations. Structure-based virtual screening was performed using the ChEMBL database. Through 1,838,257 screenings, 249 drugs (37 approved, 93 clinical, and 119 preclinical drugs) were predicted to exhibit a high binding affinity for the RdRp complex:dsRNA. Nine nucleoside triphosphate analogs with anti-viral activity were included among these hit drugs, and among them, remdesivir-ribonucleoside triphosphate and favipiravir-ribonucleoside triphosphate adopted a similar docking mode as that observed in the cryo-EM structure. Additional docking simulations for the predicted compounds with high binding affinity for the RdRp complex:dsRNA suggested that 184 bioactive compounds could be anti-SARS-CoV-2 drug candidates. The hit bioactive compounds mainly consisted of a typical noncovalent major groove binder for dsRNA. Three-layer ONIOM (MP2/6-31G:AM1:AMBER) geometry optimization calculations and frequency analyses (MP2/6-31G:AMBER) were performed to estimate the binding free energy of a representative bioactive compound obtained from the docking simulation, and the fragment molecular orbital calculation at the MP2/6-31G level of theory was subsequently performed for analyzing the detailed interactions. The procedure used in this study represents a possible strategy for discovering anti-SARS-CoV-2 drugs from drug libraries that could significantly shorten the clinical development period for drug repositioning. |
| Databáze: | OpenAIRE |
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