Targeting SARS-CoV-2 main protease (3CLpro) with Paeonia-derived phytochemicals

  • In Silico Pharmacol. 2026 Apr 17;14(2):122. doi: 10.1007/s40203-026-00630-7.
Cemal Sandalli  1 ,  Safiye Merve Bostancioglu  2 ,  Aytul Sandalli  3 ,  Emine Akyuz Turumtay  4  5 ,  Dana Almohazey  6 ,  Moneerah Alsaeed  7 ,  Galyah Alhamid  7 ,  Ali A Rabaan  8  9  10 ,  Halbay Turumtay  11  12 ,  Ei-Ichi Ami  1 ,  Christian L Lorson  1  13 ,  Mark Hannink  1 ,  Kamal Singh  1  13  14 ,  Huseyin Tombuloglu  7
Affiliations
  • 1. Christopher Bond Life Sciences Center, University of Missouri, Columbia, MO 65211 USA.
  • 2. Department of Biological Sciences, Middle East Technical University, 06800 Ankara, Türkiye.
  • 3. Department of Biology, Karadeniz Technical University, 61080 Trabzon, Türkiye.
  • 4. Department of Chemistry, Recep Tayyip Erdogan University, 53100 Rize, Türkiye.
  • 5. Technology Division, Joint BioEnergy Institute, Emeryville, CA 94608 USA.
  • 6. Department of Stem Cell Research, Institute for Research and Medical Consultations, Imam Abdulrahman Bin Faisal University, P.O. Box 1982, 31441 Dammam, Saudi Arabia.
  • 7. Department of Genetics Research, Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, P.O. Box 1982, 31441 Dammam, Saudi Arabia.
  • 8. Molecular Diagnostic Laboratory, Johns Hopkins Aramco Healthcare, Dhahran, 31311 Saudi Arabia.
  • 9. College of Medicine, Alfaisal University, Riyadh, 11533 Saudi Arabia.
  • 10. Department of Public Health and Nutrition, The University of Haripur, Haripur, 22610 Pakistan.
  • 11. Department of Energy System Engineering, Karadeniz Technical University, 61830 Trabzon, Türkiye.
  • 12. Deparment of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720 USA.
  • 13. Department of Pathobiology and Integrative Biomedical Sciences, University of Missouri, Columbia, MO 65211 USA.
  • 14. Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, 14186 Stockholm, Sweden.
PMID: 42005983 DOI: 10.1007/s40203-026-00630-7
Abstract

Coronavirus Disease 19 (COVID-19), caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), stimulated intensive drug-development efforts throughout the world. As COVID-19 has become endemic in many regions of the world, phytochemicals used in ethnomedicine may have utility in the prevention or treatment of COVID-19. Here, we employed machine learning/deep learning drug discovery tools to evaluate compounds previously identified in roots of Plants of the Paeonia genus for their drug-like properties and potential to inhibit 3CLpro, the main protease of SARS-CoV2. Our results identify Paeonia-derived compounds that have favorable drug-like properties and are predicted to have a high binding affinity for 3CLpro. Molecular dynamics simulations supported the binding affinity of Paeonia-derived compounds for 3CLpro. We validated these in silico computational results by experimentally determining the 50% inhibitory concentration (IC50) of two Paeonia-derived compounds, paeoniflorigenone and 3-O-methylquercetin, using purified 3CLpro with baicalein as a control. The IC50 values for paeoniflorigenone, 3-O-methylquercetin and baicalein were 9.33 µM, 43.94 and 43.85 µM, respectively. Root extracts from five Paeonia species were found to have minimal cytotoxicity against three different human cell types. Our results represent a proof-of-concept study demonstrating that in silico techniques, including machine and deep learning methods, can be used to identify phytochemicals as starting points for the discovery of Antiviral compounds against SARS-CoV-2.

Supplementary information: The online version contains supplementary material available at10.1007/s40203-026-00630-7.

Keywords
Paeonia; Paeoniflorigenone; Phytochemicals; SARS-CoV-2; SARS-CoV-2, 3CLpro protease.
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