Biochemical Screening of Phytochemicals and Identification of Scopoletin as a Potential Inhibitor of SARS-CoV-2 Mpro, Revealing Its Biophysical Impact on Structural Stability
Abstract
:1. Introduction
2. Materials and Methods
2.1. Virtual Screening of Selected Phytochemicals
Analysis of Molecular Interactions
2.2. Protein Expression
2.3. Protein Purification
2.4. Western Blot Analysis
2.5. FRET-Based Enzymatic Activity Assay
2.6. Fluorescence Spectroscopy
Calculation of Binding Parameters
2.7. Thermodynamic Investigation Using Isothermal Titration Calorimetry (ITC)
2.8. ADMET Analysis of Scopoletin
2.9. MD Simulation
2.10. Evaluation of Cytotoxicity by Scopoletin Using MTT Assay
3. Results
3.1. Selection of Best Phytochemical, Scopoletin, Based on Virtual Screening
3.2. Interaction Analysis
3.3. Mpro Could Be Expressed and Purified Successfully
3.4. FRET-Based Enzymatic Activity Assay Deciphers the IC50 of Scopoletin as 15.75 uM
3.5. Fluorescence Quenching of Mpro with Inhibitor Scopoletin Indicates High Affinity
3.6. CD Spectroscopy Confirmed Changes in Secondary Structure of Mpro upon Binding of Scopoletin
3.7. Isothermal Titration Calorimetry (ITC)
3.8. ADMET Analysis
3.9. MD Simulations Supported the Spectral Data at Dynamic Level
3.9.1. Dynamics of Hydrogen Bonds
3.9.2. Principal Component and Free Energy Landscape Analyses
3.10. MTT Assay of Scopoletin to Evaluate Its Cytotoxicity in HEK293 Cells
4. Discussion
Scopoletin, a Phytochemical, Is a Potential Inhibitor of Mpro and Suitable for SARS-CoV-2 Treatment
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Ligand Name | Binding Free Energy (kcal/mol) | pKi | Ligand Efficiency (kcal/mol/non-H Atom) | Torsional Energy (kcal/mol) |
---|---|---|---|---|
Scopoletin | −5.5 | 4.03 | 0.3929 | 0.6226 |
Gingerol | −4.6 | 3.37 | 0.219 | 3.7356 |
Pinine | −4.9 | 3.59 | 0.49 | 0 |
Limonene | −4.9 | 3.59 | 0.49 | 0.3113 |
Myrcene | −3.9 | 2.86 | 0.39 | 1.2452 |
Quercetin | −7.1 | 3.89 | 0.3786 | 0.6226 |
Compound and Its Chemical Structure | Conventional Hydrogen Bonds with Mpro | Carbon Hydrogen Bonds with Mpro | Van der Waals Force/Interaction/Bonds with Mpro | P-alkyl/Alkyl Bonds with Mpro |
---|---|---|---|---|
Scopoletin | TYR54 | HIS164 | HIS41, GLY143, ARG188, ASP187, GLN189, GLU166, MET165 | HIS163, CYS145, MET49 |
Quercetin | TYR54, THR26 | Nil | ASN142, HIS41, PRO52, ARG188, ASP187, GLN189, MET165, GLU166, HIS164, LEU27, GLY143 | MET49, CYS145 |
Compound ID | Absorption | Distribution | Metabolism | Excretion | Toxicity | |
---|---|---|---|---|---|---|
GI Absorption | Water Solubility | BBB permeation | CYP2D6Inh/Subs | OCT2 substrate | AMES | |
Scopoletin | High | Yes | Yes | No | No | No |
Name of the Ligand | Plant Source | Ligand Structure | Chemical Name | Biological Activities | References |
---|---|---|---|---|---|
Scopoletin | Plants from Artemisia, Scopolia, Viburnum, and Mitracarpus genus. | 6-methoxy-7-hydrocoumarian | Antiviral Anti-cancer Antimicrobial Immunomodulatory Anti-angiogenesis Anti-oxidation Neuroprotective Anti-diabetic Antihypertensive Hepatoprotective Anti-inflammatory | [41], [70,71], PubChem CID: 5,280,460 [69] |
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Bano, S.; Singh, J.; Zehra, Z.; Sulaimani, M.N.; Mohammad, T.; Yumlembam, S.; Hassan, M.I.; Islam, A.; Dey, S.K. Biochemical Screening of Phytochemicals and Identification of Scopoletin as a Potential Inhibitor of SARS-CoV-2 Mpro, Revealing Its Biophysical Impact on Structural Stability. Viruses 2025, 17, 402. https://doi.org/10.3390/v17030402
Bano S, Singh J, Zehra Z, Sulaimani MN, Mohammad T, Yumlembam S, Hassan MI, Islam A, Dey SK. Biochemical Screening of Phytochemicals and Identification of Scopoletin as a Potential Inhibitor of SARS-CoV-2 Mpro, Revealing Its Biophysical Impact on Structural Stability. Viruses. 2025; 17(3):402. https://doi.org/10.3390/v17030402
Chicago/Turabian StyleBano, Sarika, Jyotishna Singh, Zainy Zehra, Md Nayab Sulaimani, Taj Mohammad, Seemasundari Yumlembam, Md Imtaiyaz Hassan, Asimul Islam, and Sanjay Kumar Dey. 2025. "Biochemical Screening of Phytochemicals and Identification of Scopoletin as a Potential Inhibitor of SARS-CoV-2 Mpro, Revealing Its Biophysical Impact on Structural Stability" Viruses 17, no. 3: 402. https://doi.org/10.3390/v17030402
APA StyleBano, S., Singh, J., Zehra, Z., Sulaimani, M. N., Mohammad, T., Yumlembam, S., Hassan, M. I., Islam, A., & Dey, S. K. (2025). Biochemical Screening of Phytochemicals and Identification of Scopoletin as a Potential Inhibitor of SARS-CoV-2 Mpro, Revealing Its Biophysical Impact on Structural Stability. Viruses, 17(3), 402. https://doi.org/10.3390/v17030402