Integrated study of Quercetin as a potent SARS-CoV-2 RdRp inhibitor: Binding interactions, MD simulations, and In vitro assays

• Published in: PloS one 2024-12, Vol.19 (12), p.e0312866
• Main Authors: Metwaly, Ahmed M, El-Fakharany, Esmail M, Alsfouk, Aisha A, Ibrahim, Ibrahim M, Elkaeed, Eslam B, Eissa, Ibrahim H
• Format: Article
• Language: English
• Subjects: Adenosine Monophosphate - analogs & derivatives; Adenosine Monophosphate - chemistry; Adenosine Monophosphate - metabolism; Adenosine Monophosphate - pharmacology; Alanine - analogs & derivatives; Alanine - chemistry; Alanine - pharmacology; Amino acids; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Binding; Binding Sites; Bioavailability; Biology and life sciences; Comparative analysis; COVID-19; COVID-19 - metabolism; COVID-19 - virology; COVID-19 Drug Treatment; Crystallization; DNA-directed RNA polymerase; Drug discovery; Dynamic structural analysis; Effectiveness; Enzymes; Evaluation; Flavonoids; Health aspects; Humans; Hydrogen; Hydrogen bonding; Hydrogen bonds; Inhibitors; Ligands; Medicine and health sciences; Molecular docking; Molecular Docking Simulation; Molecular dynamics; Molecular Dynamics Simulation; Molecular weight; Physical Sciences; Principal components analysis; Properties; Protein Binding; Proteins; Quercetin; Quercetin - analogs & derivatives; Quercetin - chemistry; Quercetin - metabolism; Quercetin - pharmacology; Research and Analysis Methods; RNA; RNA polymerase; RNA-Dependent RNA Polymerase - antagonists & inhibitors; RNA-Dependent RNA Polymerase - chemistry; RNA-Dependent RNA Polymerase - metabolism; RNA-directed RNA polymerase; Safety margins; SARS-CoV-2 - drug effects; SARS-CoV-2 - metabolism; Severe acute respiratory syndrome coronavirus 2; Simulation; Simulation methods; Viral infections
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0312866

To find an effective inhibitor for SARS-CoV-2, Quercetin's chemical structure was compared to nine ligands associated with nine key SARS-CoV-2 proteins. It was found that Quercetin closely resembles Remdesivir, the co-crystallized ligand of RNA-dependent RNA polymerase (RdRp). This similarity was confirmed through flexible alignment experiments and molecular docking studies, which showed that both Quercetin and Remdesivir bind similarly to the active site of RdRp. Molecular dynamics (MD) simulations over a 200 ns trajectory, analyzing various factors like RMSD, RG, RMSF, SASA, and hydrogen bonding were conducted. These simulations gave detailed insights into the binding interactions of Quercetin with RdRp compared to Remdesivir. Further analyses, including MM-GBSA, Protein-Ligand Interaction Fingerprints (ProLIF) and Profile PLIP studies, confirmed the stability of Quercetin's binding. Principal component analysis of trajectories (PCAT) provided insights into the coordinated movements within the systems studied. In vitro assays showed that Quercetin is highly effective in inhibiting RdRp, with an IC50 of 122.1 ±5.46 nM, which is better than Remdesivir's IC50 of 21.62 ±2.81 μM. Moreover, Quercetin showed greater efficacy against SARS-CoV-2 In vitro, with an IC50 of 1.149 μg/ml compared to Remdesivir's 9.54 μg/ml. The selectivity index (SI) values highlighted Quercetin's safety margin (SI: 791) over Remdesivir (SI: 6). In conclusion, our comprehensive study suggests that Quercetin is a promising candidate for further research as an inhibitor of SARS-CoV-2 RdRp, providing valuable insights for developing an effective anti-COVID-19 treatment.