Computational studies of caffeoylquinic acids from Brazilian green propolis and its anti-viral potential against SARS-CoV-2 Mpro




Caffeoylquinic acids; Computer simulation; COVID-19; Propolis; SARS-CoV-2 infection.


Purpose: The present study evaluated the following caffeoylquinic acids, Neochlorogenic acid (3-CQA), Cryptochlorogenic acid (4-CQA), Chlorogenic Acid (5-CQA), Isochlorogenic acid A (3,5-DCQA) Isochlorogenic acid B (3,4-DCQA) and Isochlorogenic acid C (4,5-DCQA) found in Brazilian green propolis, regarding its physicochemical, pharmacokinetic and conformational characteristics. Additionally, the compounds were explored on the efficacy of inhibiting the pharmacological target SARS-CoV-2 Mpro, a protein involved in SARS-Cov-2 infection. Methods: The physicochemical and pharmacokinetic proprieties were obtained from the projected 2D structures of the respective compounds. The conformational characteristics were obtained from the three-dimensional models were subjected to geometric optimization by molecular mechanics under MMFF94 force field, subsequently, the calculation of partial atomic charges by employing AM1 semi-empirical methodology was performed. Molecular docking was performed, and the protein was loaded in PDB Data Bank (PDB ID 6LU7). Results: The physicochemical and pharmacokinetic results indicate that these phytochemicals have from medium to low potential for gastrointestinal tract absorption, principally in relation to the LogP values, and violated some druglikeness’ criteria. However molecular docking showed that the compounds 3-CQA, 4-CQA, 5-CQA, 3,5-DCQA, 3,4-DCQA and 4,5-DCQA potentially binds with the active site of the SARS-CoV-2 Mpro, through stables complexes, with a docking score of -6.44, -6.11, -6.48, -6.26, -7.01 and -7.40 kcal/mol, respectively. Conclusion: The physicochemical and pharmacokinetic parameters, as well as Hydrogen-bond formation, energy landscape, indicate that the compound with the greatest therapeutic potential are 5-CQA, 3,4-DCQA and 4,5-DCQA however this study necessitates further in vitro and in vivo experimental validation.


Ali, A. M., & Kunugi, H. (2021). Propolis, bee honey, and their components protect against coronavirus disease 2019 (Covid-19): A review of in silico, in vitro, and clinical studies. Molecules, 26(5).

Arafet, K., Serrano-Aparicio, N., Lodola, A., Mulholland, A. J., González, F. V, Świderek, K., & Moliner, V. (2021). Mechanism of inhibition of SARS-CoV-2 Mpro by N3 peptidyl Michael acceptor explained by QM/MM simulations and design of new derivatives with tunable chemical reactivity. Chemical Science, 12(4), 1433–1444.

Baell, J. B., & Holloway, G. A. (2010). New Substructure Filters for Removal of Pan Assay Interference Compounds (PAINS) from Screening Libraries and for Their Exclusion in Bioassays. Journal of Medicinal Chemistry, 53(7), 2719–2740.

Berretta, A. A., Silveira, M. A. D., Cóndor Capcha, J. M., & De Jong, D. (2020). Propolis and its potential against SARS-CoV-2 infection mechanisms and COVID-19 disease: Running title: Propolis against SARS-CoV-2 infection and COVID-19. Biomedicine and Pharmacotherapy, 131, 110622.

Bezerra, C. R. F., Assunção Borges, K. R., Alves, R. de N. S., Teles, A. M., Pimentel Rodrigues, I. V., da Silva, M. A. C. N., Nascimento, M. do D. S. B., & Bezerra, G. F. de B. (2020). Highly efficient antibiofilm and antifungal activity of green propolis against Candida species in dentistry materials. PLOS ONE, 15(12), e0228828.

Brenk, R., Schipani, A., James, D., Krasowski, A., Gilbert, I. H., Frearson, J., & Wyatt, P. G. (2008). Lessons Learnt from Assembling Screening Libraries for Drug Discovery for Neglected Diseases. ChemMedChem, 3(3), 435–444.

Chae, S. Y., Jang, M.-K., & Nah, J.-W. (2005). Influence of molecular weight on oral absorption of water soluble chitosans. Journal of Controlled Release : Official Journal of the Controlled Release Society, 102(2), 383–394.

Clark, D. E. (1999). Rapid calculation of polar molecular surface area and its application to the prediction of transport phenomena. 1. Prediction of intestinal absorption. Journal of Pharmaceutical Sciences, 88(8), 807–814.

Coimbra, J. T. S., Feghali, R., Ribeiro, R. P., Ramos, M. J., & Fernandes, P. A. (2021). The importance of intramolecular hydrogen bonds on the translocation of the small drug piracetam through a lipid bilayer. RSC Advances, 11(2), 899–908.

Daina, A., Michielin, O., & Zoete, V. (2014). iLOGP: A Simple, Robust, and Efficient Description of n-Octanol/Water Partition Coefficient for Drug Design Using the GB/SA Approach. Journal of Chemical Information and Modeling, 54(12), 3284–3301.

Daina, A., Michielin, O., & Zoete, V. (2017). SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Scientific Reports, 7(1), 42717.

De Oliveira, D. M., & Bastos, D. H. M. (2011). Biodisponibilidade de Ácidos fenólicos. Quimica Nova, 34(6), 1051–1056.

Ding, Y., Cao, Z., Cao, L., Ding, G., Wang, Z., & Xiao, W. (2017). Antiviral activity of chlorogenic acid against influenza A (H1N1/H3N2) virus and its inhibition of neuraminidase. Scientific Reports, 7(1), 45723.

Dolabela, M. F., Da Silva, A. R. P., Ohashi, L. H., Bastos, M. L. C., Da Silva, M. C. M., & Vale, V. V. (2018). Estudo in silico das atividades de triterpenos e iridoides isolados de Himatanthus articulatus (Vahl) Woodson. Revista Fitos, 12(3), 227.

Egan, W. J., Merz Kenneth M., & Baldwin, J. J. (2000). Prediction of Drug Absorption Using Multivariate Statistics. Journal of Medicinal Chemistry, 43(21), 3867–3877.

Freudenberg, K. (1920). Über Gerbstoffe. III. Chlorogensäure, der gerbstoff-artige Bestandteil der Kaffeebohnen. Berichte Der Deutschen Chemischen Gesellschaft (A and B Series), 53(2), 232–239.

Ghose, A. K., Viswanadhan, V. N., & Wendoloski, J. J. (1999). A knowledge-based approach in designing combinatorial or medicinal chemistry libraries for drug discovery. 1. A qualitative and quantitative characterization of known drug databases. Journal of Combinatorial Chemistry, 1(1), 55–68.

Jackson, P. A., Widen, J. C., Harki, D. A., & Brummond, K. M. (2017). Covalent Modifiers: A Chemical Perspective on the Reactivity of α,β-Unsaturated Carbonyls with Thiols via Hetero-Michael Addition Reactions. Journal of Medicinal Chemistry, 60(3), 839–885.

Keretsu, S., Bhujbal, S. P., & Cho, S. J. (2020). Rational approach toward COVID-19 main protease inhibitors via molecular docking, molecular dynamics simulation and free energy calculation. Scientific Reports, 10(1), 17716.

Khanna, V., & Ranganathan, S. (2009). Physiochemical property space distribution among human metabolites, drugs and toxins. BMC Bioinformatics, 10 Suppl 1(Suppl 15), S10–S10.

Kimoto, T., Arai, S., Kohguchi, M., Aga, M., Nomura, Y., Micallef, M. J., Kurimoto, M., & Mito, K. (1998). Apoptosis and suppression of tumor growth by artepillin C extracted from Brazilian propolis. Cancer Detection and Prevention, 22(6), 506–515.

Klein, P., Johe, P., Wagner, A., Jung, S., Kühlborn, J., Barthels, F., Tenzer, S., Distler, U., Waigel, W., Engels, B., Hellmich, U. A., Opatz, T., & Schirmeister, T. (2020). New Cysteine Protease Inhibitors: Electrophilic (Het)arenes and Unexpected Prodrug Identification for the Trypanosoma Protease Rhodesain. Molecules (Basel, Switzerland), 25(6), 1451.

Konishi, Y., Zhao, Z., & Shimizu, M. (2006). Phenolic acids are absorbed from the rat stomach with different absorption rates. Journal of Agricultural and Food Chemistry, 54(20), 7539–7543.

Lafay, S., Gil-Izquierdo, A., Manach, C., Morand, C., Besson, C., & Scalbert, A. (2006). Chlorogenic acid is absorbed in its intact form in the stomach of rats. The Journal of Nutrition, 136(5), 1192–1197.

Leeson, P. D., & Springthorpe, B. (2007). The influence of drug-like concepts on decision-making in medicinal chemistry. Nature Reviews Drug Discovery, 6(11), 881–890.

Leo, A., Hansch, C., & Elkins, D. (1971). Partition coefficients and their uses. Chemical Reviews, 71(6), 525–616.

Li, Y., But, P. P. H., & Ooi, V. E. C. (2005). Antiviral activity and mode of action of caffeoylquinic acids from Schefflera heptaphylla (L.) Frodin. Antiviral Research, 68(1), 1–9.

Lipinski, C. A., Lombardo, F., Dominy, B. W., & Feeney, P. J. (2001). Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Advanced Drug Delivery Reviews, 46(1–3), 3–26.

Lupatini, N. R. J., Danopoulos, P., Swikidisa, R., & Alves, P. V. (2016). Evaluation of the Antibacterial Activity of Green Propolis Extract and Meadowsweet Extract Against Staphylococcus aureus Bacteria: Importance in Would Care Compounding Preparations. International Journal of Pharmaceutical Compounding, 20(4), 333–337.

Machado, J. L., Assunção, A. K. M., da Silva, M. C. P., Dos Reis, A. S., Costa, G. C., & Arruda, D de S. (2012). Brazilian green propolis: anti-inflammatory property by an immunomodulatory activity. Evid Based Complement Alternat Med, 157652.

Mahmood, N., Moore, P. S., De Tommasi, N., De Simone, F., Colman, S., Hay, A. J., & Pizza, C. (1993). Inhibition of HIV infection by caffeoylquinic acid derivatives. Antiviral Chemistry and Chemotherapy, 4(4), 235–240.

Malone, B., Urakova, N., Snijder, E. J., & Campbell, E. A. (2022). Structures and functions of coronavirus replication–transcription complexes and their relevance for SARS-CoV-2 drug design. Nature Reviews Molecular Cell Biology, 23(1), 21–39.

Marcucci, M. C. (1995). Propolis: chemical composition, biological properties and therapeutic activity. Apidologie, 26(2), 83–99.

Maruta, H., & He, H. (2020). PAK1-blockers: Potential Therapeutics against COVID-19. Medicine in Drug Discovery, 6, 100039.

Mateos, R., Goya, L., & Bravo, L. (2006). Uptake and metabolism of hydroxycinnamic acids (chlorogenic, caffeic, and ferulic acids) by HepG2 cells as a model of the human liver. Journal of Agricultural and Food Chemistry, 54(23), 8724–8732.

Muegge, I., Heald, S. L., & Brittelli, D. (2001). Simple Selection Criteria for Drug-like Chemical Matter. Journal of Medicinal Chemistry, 44(12), 1841–1846.

Mulliner, D., Wondrousch, D., & Schüürmann, G. (2011). Predicting Michael-acceptor reactivity and toxicity through quantum chemical transition-state calculations. Organic Biomolecular Chemistry, 9(24), 8400–8412.

Olthof, M. R., Hollman, P. C. H., & Katan, M. B. (2001). Chlorogenic Acid and Caffeic Acid Are Absorbed in Humans. The Journal of Nutrition, 131(1), 66–71.

Pajouhesh, H., & Lenz, G. R. (2005). Medicinal chemical properties of successful central nervous system drugs. NeuroRx : The Journal of the American Society for Experimental NeuroTherapeutics, 2(4), 541–553.

Parker, G. R. (1978). Correlation of LogP with molecular connectivity in hydroxyureas: Influence of conformational system on log p. Journal of Pharmaceutical Sciences, 67(4), 513–516.

Prasanna, S., & Doerksen, R. J. (2009). Topological polar surface area: a useful descriptor in 2D-QSAR. Current Medicinal Chemistry, 16(1), 21–41.

Rechner, A. R., Spencer, J. P. E., Kuhnle, G., Hahn, U., & Rice-Evans, C. A. (2001). Novel biomarkers of the metabolism of caffeic acid derivatives in vivo. Free Radical Biology and Medicine, 30(11), 1213–1222.

Refaat, H., Mady, F. M., Sarhan, H. A., Rateb, H. S., & Alaaeldin, E. (2021). Optimization and evaluation of propolis liposomes as a promising therapeutic approach for COVID-19. International Journal of Pharmaceutics, 592(October), 120028.

Rocha, G. B., Freire, R. O., Simas, A. M., & Stewart, J. J. P. (2006). RM1: A reparameterization of AM1 for H, C, N, O, P, S, F, Cl, Br, and I. Journal of Computational Chemistry, 27(10), 1101–1111.

Saakre, M., Mathew, D., & Ravisankar, V. (2021). Perspectives on plant flavonoid quercetin-based drugs for novel SARS-CoV-2. Beni-Suef University Journal of Basic and Applied Sciences, 10(1), 21.

Silveira, M. A. D., De Jong, D., Berretta, A. A., Galvão, E. B. dos S., Ribeiro, J. C., Cerqueira-Silva, T., Amorim, T. C., Conceição, L. F. M. R. da, Gomes, M. M. D., Teixeira, M. B., Souza, S. P. de, Santos, M. H. C. A. dos, San Martin, R. L. A., Silva, M. de O., Lírio, M., Moreno, L., Sampaio, J. C. M., Mendonça, R., Ultchak, S. S., & Passos, R. da H. (2021). Efficacy of Brazilian green propolis (EPP-AF®) as an adjunct treatment for hospitalized COVID-19 patients: A randomized, controlled clinical trial. Biomedicine Pharmacotherapy, 138, 111526.

Stefaniak, M., Niestrój, A., Klupsch, J., Śliwiok, J., & Pyka, A. (2005). Use of RP-TLC to Determine the log P Values of Isomers of Organic Compounds. Chromatographia, 62(1), 87–89.

Urushisaki, T., Takemura, T., Tazawa, S., Fukuoka, M., Hosokawa-Muto, J., Araki, Y., & Kuwata, K. (2011). Caffeoylquinic acids are major constituents with potent anti-influenza effects in brazilian green propolis water extract. Evidence-Based Complementary and Alternative Medicine : ECAM, 2011, 254914.

Uthuppan, J., & Soni, K. (2013). Conformational Analysis: a Review. International Journal of Pharmaceutical Sciences and Research, 4(1), 34–41.

Veber, D. F., Johnson, S. R., Cheng, H.-Y., Smith, B. R., Ward, K. W., & Kopple, K. D. (2002). Molecular Properties That Influence the Oral Bioavailability of Drug Candidates. Journal of Medicinal Chemistry, 45(12), 2615–2623.

Veiga, R. S., De Mendonça, S., Mendes, P. B., Paulino, N., Mimica, M. J., Lagareiro Netto, A. A., Lira, I. S., López, B. G.-C., Negrão, V., & Marcucci, M. C. (2017). Artepillin C and phenolic compounds responsible for antimicrobial and antioxidant activity of green propolis and Baccharis dracunculifolia DC. Journal of Applied Microbiology, 122(4), 911–920.

Verheij, H. J. (2006). Leadlikeness and structural diversity of synthetic screening libraries. Molecular Diversity, 10(3), 377–388.

Worldometers. (2022). COVID-19 Coronavirus Pandemic. COVID-19 Coronavirus Pandemic.

Zhang, G., & Musgrave, C. B. (2007). Comparison of DFT Methods for Molecular Orbital Eigenvalue Calculations. The Journal of Physical Chemistry A, 111(8), 1554–1561.

Zhao, Y. H., Abraham, M. H., Le, J., Hersey, A., Luscombe, C. N., Beck, G., Sherborne, B., & Cooper, I. (2002). Rate-Limited Steps of Human Oral Absorption and QSAR Studies. Pharmaceutical Research, 19(10), 1446–1457.

Zulhendri, F., Chandrasekaran, K., Kowacz, M., Ravalia, M., Kripal, K., Fearnley, J., & Perera, C. O. (2021). Properties of Propolis : A Review. 1–29.




How to Cite

GONÇALVES, C. P. .; MARCUCCI, M. C.; ROCHA, O. V. .; UTUARI, C. L. C. .; FORTUNATO, C. R. M. .; SOUZA, G. F. de .; FARIAS, A. Computational studies of caffeoylquinic acids from Brazilian green propolis and its anti-viral potential against SARS-CoV-2 Mpro. Research, Society and Development, [S. l.], v. 11, n. 15, p. e359111536917, 2022. DOI: 10.33448/rsd-v11i15.36917. Disponível em: Acesso em: 9 feb. 2023.



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