In Silico Evaluation of Natural Phenolic Compounds Targeting the S1P1 Receptor and Cardiovascular-Related Protein Targets: Molecular Docking and ADMET Analysis

Öz

The aim of this study was to evaluate the potential interactions of selected phenolic compounds with the S1P1 receptor and cardiovascular-related protein targets using molecular docking, and to investigate their pharmacokinetic and toxicological properties via in silico ADMET analysis. Six different protein structures (PDB: 3VY2, 7C4S, 7TD3, 7VIE, 7VIF and 7WF7) were obtained from the Protein Data Bank database. Apigenin, fisetin, kaempferol, quercetin, resveratrol and rosmarinic acid were used as ligands. Molecular docking analyses were performed using AutoDock Vina software, and the most suitable binding positions were determined based on RMSD and binding energies. Furthermore, ADMET properties were evaluated using ADMETlab 3.0. All compounds exhibited suitable binding affinity for the selected protein targets. Docking scores ranged from -7.2 to -9.3 kcal/mol. Apigenin and rosmarinic acid demonstrated stronger and more consistent binding profiles compared to the other compounds. Interaction analyses have shown that hydrogen bonds, π–π interactions and hydrophobic contacts play a significant role in complex stability. According to ADMET analysis, apigenin exhibited better membrane permeability, whilst rosmarinic acid presented a more stable metabolic profile. The findings suggest that apigenin and rosmarinic acid, in particular, may be potential therapeutic candidates for the S1P1 receptor and cardiovascular-associated proteins. However, further in vitro and in vivo studies are required to validate these results.

Anahtar Kelimeler

• Molecular docking
• Natural polyphenols
• Cardiovascular diseases
• Endothelial function
• Cellular perfusion
• Vascular biology

Etik Beyan

Ethics committee approval was not obtained as no studies on animals or humans were conducted in this study.

Kaynakça

1. Alagawany, M., Abd El-Hack, M. E., Farag, M. R., Gopi, M., Karthik, K., Malik, Y. S., & Dhama, K. (2017). Rosmarinic acid: modes of action, medicinal values and health benefits. Animal health research reviews, 18(2), 167–176. https://doi.org/10.1017/S1466252317000081
2. Aoki, M., Aoki, H., Ramanathan, R., Hait, N. C., & Takabe, K. (2016). Sphingosine‐1‐phosphate signaling in immune cells and inflammation: Roles and therapeutic potential. Mediators of Inflammation, 2016(1), Article 8606878. https://doi.org/10.1155/2016/8606878
3. Cartier, A., & Hla, T. (2019). Sphingosine 1-phosphate: Lipid signaling in pathology and therapy. Science (New York, N.Y.), 366(6463), eaar5551. https://doi.org/10.1126/science.aar5551
4. Clayton, Z. S., Hutton, D. A., Brunt, V. E., VanDongen, N. S., Ziemba, B. P., Casso, A. G., Greenberg, N. T., Mercer, A. N., Rossman, M. J., Campisi, J., Melov, S., & Seals, D. R. (2021). Apigenin restores endothelial function by ameliorating oxidative stress, reverses aortic stiffening, and mitigates vascular inflammation with aging. American Journal of Physiology - Heart and Circulatory Physiology, 321(1), H185–H196. https://doi.org/10.1152/ajpheart.00118.2021
5. Dhalla, N. S., Temsah, R. M., & Netticadan, T. (2000). Role of oxidative stress in cardiovascular diseases. Journal of Hypertension, 18(6), 655–673. https://doi.org/10.1097/00004872-200018060-00002
6. Diedrich, K., Krause, B., Berg, O., & Rarey, M. (2023). PoseEdit: Enhanced ligand binding mode communication by interactive 2D diagrams. Journal of Computer-Aided Molecular Design, 37(10), 491–503. https://doi.org/10.1007/s10822-023-00524-2
7. Dikme, T. G., Necip, A., Dikme, R., & Güneş, S. (2024). Effect of phytosterols in apricot kernel on cholesterol: Molecular docking. Mehes Journal, 2(3), 28–38.
8. Dong, J., Wang, N. N., Yao, Z. J., Zhang, L., Cheng, Y., Ouyang, D., Lu, A. P., & Cao, D. S. (2018). ADMETlab: A platform for systematic ADMET evaluation based on a comprehensively collected ADMET database. Journal of Cheminformatics, 10(1), Article 29. https://doi.org/10.1186/s13321-018-0283-x

9. Duan, Y., Leong, N. C., Zhao, J., Zhang, Y., Nguyen, D. T., Ha, H. T., Wang, L., Zhou, M., & He, Y. (2024). Structural basis of sphingosine-1-phosphate transport via human SPNS2. Cell Research, 34(2), 177–180. https://doi.org/10.1038/s41422-023-00913-9
10. Dubois-Deruy, E., Peugnet, V., Turkieh, A., & Pinet, F. (2020). Oxidative stress in cardiovascular diseases. Antioxidants, 9(9), Article 864. https://doi.org/10.3390/antiox9090864
11. Fassett, R. G., & Coombes, J. S. (2009). Astaxanthin, oxidative stress, inflammation and cardiovascular disease. Future Cardiology, 5(4), 333–342. https://doi.org/10.2217/fca.09.19
12. Ferreira, L. G., Dos Santos, R. N., Oliva, G., & Andricopulo, A. D. (2015). Molecular docking and structure-based drug design strategies. Molecules (Basel, Switzerland), 20(7), 13384–13421. https://doi.org/10.3390/molecules200713384
13. Gleeson, M. P. (2008). Generation of a set of simple, interpretable ADMET rules of thumb. Journal of Medicinal Chemistry, 51(4), 817–834. https://doi.org/10.1021/jm701122q
14. Guan, H., Luo, W., Bao, B., Cao, Y., Cheng, F., Yu, S., Fan, Q., Zhang, L., Wu, Q., & Shan, M. (2022). A Comprehensive Review of Rosmarinic Acid: From Phytochemistry to Pharmacology and Its New Insight. Molecules (Basel, Switzerland), 27(10), 3292. https://doi.org/10.3390/molecules27103292
15. İzol, E., Beltekin, B., Turhan, M., Karakoç, Ş., Necip, A., Yılmaz, M. A., Ertürk, M., & Çakır, O. (2026). Comprehensive exploration of three pistachio varieties: Antidiabetic, anticholinergic, antioxidant properties, phytochemical profile by LC–MS/MS, and molecular docking. Food Science & Nutrition, 14(3), Article e71656. https://doi.org/10.1002/fsn3.71656
16. İzol, E., Turhan, M., Yapıcı, İ., Necip, A., Yılmaz, M. A., & Zengin, G. (2025). Research of Peganum harmala: Phytochemical content, mineral profile, antioxidant, antidiabetic, anticholinergic properties, and molecular docking. Chemistry & Biodiversity, 22(7), Article e202403178. https://doi.org/10.1002/cbdv.202403178
17. Kitamura, M., Kojima, S., Ogasawara, K., Nakaya, T., Sagara, T., Niki, K., Miura, K., Akutsu, H., & Kumagai, I. (1994). Novel FMN-binding protein from Desulfovibrio vulgaris (Miyazaki F): Cloning and expression of its gene in Escherichia coli. The Journal of Biological Chemistry, 269(8), 5566–5573.
18. 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. https://doi.org/10.1016/s0169-409x(00)00129-0
19. Liu, S., Paknejad, N., Zhu, L., Kihara, Y., Ray, M., Chun, J., Liu, W., Hite, R. K., & Huang, X. Y. (2022). Differential activation mechanisms of lipid GPCRs by lysophosphatidic acid and sphingosine 1-phosphate. Nature Communications, 13(1), Article 731. https://doi.org/10.1038/s41467-022-28417-2
20. Maeda, S., Shiimura, Y., Asada, H., Hirata, K., Luo, F., Nango, E., Tanaka, N., Toyomoto, M., Inoue, A., Aoki, J., Iwata, S., & Hagiwara, M. (2021). Endogenous agonist-bound S1PR3 structure reveals determinants of G protein-subtype bias. Science Advances, 7(24), Article eabf5325. https://doi.org/10.1126/sciadv.abf5325
21. Morris, G. M., Huey, R., Lindstrom, W., Sanner, M. F., Belew, R. K., Goodsell, D. S., & Olson, A. J. (2009). AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. Journal of Computational Chemistry, 30(16), 2785–2791. https://doi.org/10.1002/jcc.21256
22. Necip, A. (2025). Natural remedies for type 2 diabetes: Evaluation of phytochemicals with bioinformatics and molecular approaches/ADME/T analysis. Cumhuriyet Science Journal, 46(2), 329–337. https://doi.org/10.37775/csj.1504123
23. Noor, S., Mohammad, T., Rub, M. A., Raza, A., Azum, N., Yadav, D. K., Hassan, M. I., & Asiri, A. M. (2022). Biomedical features and therapeutic potential of rosmarinic acid. Archives of pharmacal research, 45(4), 205–228. https://doi.org/10.1007/s12272-022-01378-2
24. Panche, A. N., Diwan, A. D., & Chandra, S. R. (2016). Flavonoids: An overview. Journal of Nutritional Science, 5, Article e47. https://doi.org/10.1017/jns.2016.41
25. Petersen, M., & Simmonds, M. S. (2003). Rosmarinic acid. Phytochemistry, 62(2), 121–125. https://doi.org/10.1016/s0031-9422(02)00513-7
26. Pettersen, E. F., Goddard, T. D., Huang, C. C., Couch, G. S., Greenblatt, D. M., Meng, E. C., & Ferrin, T. E. (2004). UCSF Chimera—A visualization system for exploratory research and analysis. Journal of Computational Chemistry, 25(13), 1605–1612. https://doi.org/10.1002/jcc.20084
27. Pickering, R. J. (2021). Oxidative stress and inflammation in cardiovascular diseases. Antioxidants, 10(2), Article 171. https://doi.org/10.3390/antiox10020171
28. Pires, D. E., Blundell, T. L., & Ascher, D. B. (2015). pkCSM: Predicting small-molecule pharmacokinetic and toxicity properties using graph-based signatures. Journal of Medicinal Chemistry, 58(9), 4066–4072. https://doi.org/10.1021/acs.jmedchem.5b00104
29. Proia, R. L., & Hla, T. (2015). Emerging biology of sphingosine-1-phosphate: its role in pathogenesis and therapy. The Journal of clinical investigation, 125(4), 1379–1387. https://doi.org/10.1172/JCI76369
30. Pundir, A., Choudhary, D., Dhama, K., Kumar, P., Sood, S., Seth, P., Sharma, N., El-Ansary, A., & Tuli, H. S. (2022). Molecular docking studies of apigenin, kaempferol, and quercetin as potential target against spike receptor protein of SARS COV. Journal of Experimental Biology and Agricultural Sciences, 10(1), 144–149. http://dx.doi.org/10.18006/2022.10(1).144.149
31. Rose, P. W., Prlić, A., Bi, C., Bluhm, W. F., Christie, C. H., Dutta, S., Micallef, V., Voigt, M., Westbrook, J., Young, J., & Burley, S. K. (2015). The RCSB Protein Data Bank: Views of structural biology for basic and applied research and education. Nucleic Acids Research, 43(D1), D345–D356. https://doi.org/10.1093/nar/gku1214
32. Salehi, B., Venditti, A., Sharifi-Rad, M., Kręgiel, D., Sharifi-Rad, J., Durazzo, A., Lucarini, M., Santini, A., Souto, E. B., Novellino, E., Antolak, H., Azzini, E., Setzer, W. N., & Martins, N. (2019). The therapeutic potential of apigenin. International Journal of Molecular Sciences, 20(6), Article 1305. https://doi.org/10.3390/ijms20061305
33. Senoner, T., & Dichtl, W. (2019). Oxidative stress in cardiovascular diseases: Still a therapeutic target?. Nutrients, 11(9), Article 2090. https://doi.org/10.3390/nu11092090
34. Stierand, K., & Rarey, M. (2010). PoseView—Molecular interaction patterns at a glance. Journal of Cheminformatics, 2(Suppl 1), Article P50. https://doi.org/10.1186/1758-2946-2-S1-P50
35. Wang, M., Firrman, J., Liu, L., & Yam, K. (2019). A review on flavonoid apigenin: Dietary intake, ADME, antimicrobial effects, and interactions with human gut microbiota. BioMed Research International, 2019(1), Article 7010467. https://doi.org/10.1155/2019/7010467
36. Xiong, G., Wu, Z., Yi, J., Fu, L., Yang, Z., Hsieh, C., Yin, M., Zeng, X., Wu, C., Lu, A., Chen, X., Hou, T., & Cao, D. (2021). ADMETlab 2.0: An integrated online platform for accurate and comprehensive predictions of ADMET properties. Nucleic Acids Research, 49(W1), W5–W14. https://doi.org/10.1093/nar/gkab255
37. Xu, Z., Ikuta, T., Kawakami, K., Kise, R., Qian, Y., Xia, R., Sun, M. X., Zhang, A., Guo, C., Cai, X. H., Huang, Z., Inoue, A., & He, Y. (2022). Structural basis of sphingosine-1-phosphate receptor 1 activation and biased agonism. Nature Chemical Biology, 18(3), 281–288. https://doi.org/10.1038/s41589-021-00930-3
38. Yildirim, M., Necip, A., Cimentepe, M., Emire, Z., & Yabalak, E. (2025). Bioactive potential of Origanum munzurense Kit Tan & Sorger extracts: Antioxidant, anticancer, and antibacterial activities explored through Sc-CO2 extraction and molecular docking analysis. Journal of Chromatography B, 1259, Article 124614. https://doi.org/10.1016/j.jchromb.2025.124614
39. Yu, L., He, L., Gan, B., Ti, R., Xiao, Q., Hu, H., Zhu, L., Wang, S., & Ren, R. (2022). Structural insights into sphingosine-1-phosphate receptor activation. Proceedings of the National Academy of Sciences, 119(16), Article e2117716119. https://doi.org/10.1073/pnas.2117716119