ICOPMAP SPECIAL EDITION Virtual screening of metabolites from mulberry (Morus alba L.) leaves as anti-hyperglycemic agents through molecular docking against multiple targets
DOI:
https://doi.org/10.46542/pe.2025.252.814Keywords:
Anti-hyperglycemic, Docking study, Morus alba L., Sanggenol M, Virtual screeningAbstract
Background: Mulberry (Morus alba L.) leaves have been widely studied as an anti-hyperglycemic agent. However, the mechanism of action and metabolites responsible for their anti-hyperglycemic activity are not yet known.
Objective: This research aims to virtually screen active compounds from mulberry leaves using the molecular docking method against multi-targets related to hyperglycemia activity.
Method: A total of 157 metabolites from mulberry leaves were made into 10 conformers and docked by using PLANTS against 12 different targets. Three best compounds for each target were then filtered, analyzed based on Lipinski’s rule of five, and plotted into a BOILED-Egg diagram to analyze their oral bioavailability.
Result: Sixteen compounds dominated the top ranking of docking scores against 12 different targets. Sanggenol M is one of the most promising compounds that are capable of scoring a high ranker in 7 different targets: α-glucosidase, dipeptidyl peptidase-4, free fatty acid receptors-1, glycogen phosphorylase, glucagon receptor, ATP-sensitive potassium channel, and AMP-activated protein kinase. However, Lipinski’s rule of five and BOILED-Egg diagram analysis predicted that Sanggenol M has poor oral bioavailability.
Conclusion: Sanggenol M has a good potential to be developed into an antihyperglycemic agent and further development needs to be done to increase its oral bioavailability.
References
Aelenei, P., Luca, S. V., Horhogea, C. E., Rimbu, C. M., Dimitriu, G., Macovei, I., Silion, M., Aprotosoaie, A. C., & Miron, A. (2019). Morus alba leaf extract: Metabolite profiling and interactions with antibiotics against Staphylococcus spp. including MRSA. Phytochemistry Letters, 31(April), 217–224. https://doi.org/10.1016/j.phytol.2019.04.006
Daina, A., & Zoete, V. (2016). A BOILED-Egg to predict gastrointestinal absorption and brain penetration of small molecules. ChemMedChem, 11(11), 1117–1121. https://doi.org/10.1002/cmdc.201600182
Eckhardt, M., Langkopf, E., Mark, M., Tadayyon, M., Thomas, L., Nar, H., Pfrengle, W., Guth, B., Lotz, R., Sieger, P., Fuchs, H., & Himmelsbach, F. (2007). 8-(3-(R)-aminopiperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin- 2-ylmethyl)-3,7-dihydropurine-2,6-dione (BI 1356), a highly potent, selective, long-acting, and orally bioavailable DPP-4 inhibitor for the treatment of type 2 diabetes. Journal of Medicinal Chemistry, 50(26), 6450–6453. https://doi.org/10.1021/jm701280z
Eisenmann, M., Steuber, H., Zentgraf, M., Altenkämper, M., Ortmann, R., Perruchon, J., Klebe, G., & Schlitzer, M. (2009). Structure-based optimization of aldose reductase inhibitors originating from virtual screening. ChemMedChem, 4(5), 809–819. https://doi.org/10.1002/cmdc.200800410
Gellrich, L., Heitel, P., Heering, J., …. & Merk, D. (2020). L-Thyroxin and the nonclassical thyroid hormone TETRAC are potent activators of PPARÎ. Journal of Medicinal Chemistry, 63(13), 6727–6740. https://doi.org/10.1021/acs.jmedchem.9b02150
Griffith, D. A., Edmonds, D. J., Fortin, J. P., … & Tess, D. A. (2022). A small-molecule oral agonist of the human glucagon-like peptide-1 receptor. Journal of Medicinal Chemistry, 65(12), 8208–8226. https://doi.org/10.1021/acs.jmedchem.1c01856
Han, X., Song, C., Feng, X., Wang, Y., Meng, T., Li, S., Bai, Y., Du, B., & Sun, Q. (2020). Isolation and hypoglycemic effects of water extracts from mulberry leaves in Northeast China. Food and Function, 11(4), 3112–3125. https://doi.org/10.1039/d0fo00012d
Hiraizumi, M., Akashi, T., Murasaki, K., Kishida, H., Kumanomidou, T., Torimoto, N., Nureki, O., & Miyaguchi, I. (2024). Transport and inhibition mechanism of the human SGLT2–MAP17 glucose transporter. Nature Structural and Molecular Biology, 31(1), 159–169. https://doi.org/10.1038/s41594-023-01134-0
Jan, B., Zahiruddin, S., Basist, P., Irfan, M., Abass, S., & Ahamad, S. (2022). Metabolomic profiling and identification of antioxidant and antidiabetic compounds from leaves of different varieties of Morus alba Linn grown in Kashmir. ACS Omega, 7(28), 24317–24328. https://doi.org/10.1021/acsomega.2c01623
Ministry of Health Republic of Indonesia. (2023). Indonesian Health Survey (SKI) in numbers. https://repository.badankebijakan.kemkes.go.id/id/eprint/5539vv
Ko, W., Liu, Z., Kim, K., Dong, L., Lee, H., Kim, N. Y., Lee, D., & Woo, E. (2021). Kuwanon t and sanggenon a isolated from morus alba exert anti-inflammatory effects by regulating nf-κb and ho-1/nrf2 signaling pathways in bv2 and raw264.7 cells. Molecules, 26(24), 7642. https://doi.org/10.3390/molecules26247642vv
Korb, O., Stützle, T., & Exner, T. E. (2006). PLANTS: Application of ant colony optimization to structure-based drug design. Lecture Notes in Computer Science (Including Subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics), 4150, 247–258. https://doi.org/10.1007/11839088_22
Miladiyah, I., Jumina, J., Haryana, S. M., & Mustofa, M. (2017). In silico molecular docking of xanthone derivatives as cyclooxygenase-2 inhibitor agents. International Journal of Pharmacy and Pharmaceutical Sciences, 9(3), 98. https://doi.org/10.22159/ijpps.2017v9i3.15382
Morales Ramos, J. G., Esteves Pairazamán, A. T., Mocarro Willis, M. E. S., Collantes Santisteban, S., & Caldas Herrera, E. (2021). Medicinal properties of Morus alba for the control of type 2 diabetes mellitus: A systematic review. F1000Research, 10, 1022. https://doi.org/10.12688/f1000research.55573.1
Novida, H., Soelistyo, S. A., Cahyani, C., Siagian, N., Hadi, U., & Pranoto, A. (2023). Factors associated with disease severity of COVID-19 in patients with type 2 diabetes mellitus. Biomedical Reports, 18(1), 8. https://doi.org/10.3892/br.2022.1590
Ovens, A. J., Gee, Y. S., Ling, N. X. Y., … & Langendorf, C. G. (2022). Structure-function analysis of the AMPK activator SC4 and identification of a potent pan AMPK activator. Biochemical Journal, 479(11), 1181–1204. https://doi.org/10.1042/BCJ20220067vv
Park, C. H., Park, Y. E., Yeo, H. J., Yoon, J. S., Park, S-Y., Kim, J. K., & Park, S. U. (2021). Comparative analysis of secondary metabolites and metabolic profiling between diploid and tetraploid Morus alba L. Journal of Agricultural and Food Chemistry, 69(4), 1300–1307. https://doi.org/10.1021/acs.jafc.0c06863
Ramírez, D., & Caballero, J. (2018). Is it reliable to take the molecular docking top scoring position as the best solution without considering available structural data? Molecules, 23(5), 1038. https://doi.org/10.3390/molecules23051038
Ren, X., Sun, Y., Guo, Q., Liu, H., Jiang, H., He, X., Li, X., Shi, X., Xiu, Z., & Dong, Y. (2022). Ameliorating effect of the total flavonoids of Morus nigra L. on prediabetic mice based on regulation of inflammation and insulin sensitization. Journal of Agricultural and Food Chemistry, 70(39), 12484–12501. https://doi.org/10.1021/acs.jafc.2c04970
Salem, M. A., Salama, M. M., Ezzat, S. M., & Hashem, Y. A. (2022). Comparative metabolite profiling of four polyphenol rich Morus leaves extracts in relation to their antibiofilm activity against Enterococcus faecalis. Scientific Reports, 12(1), 20168. https://doi.org/10.1038/s41598-022-24382-4
Sándor, M., Kiss, R., & Keseru, G. M. (2010). Virtual fragment docking by glide: A validation study on 190 protein-fragment complexes. Journal of Chemical Information and Modeling, 50(6), 1165–1172. https://doi.org/10.1021/ci1000407
Silva, D. H. A. da, Barbosa, H. de M., Beltrão, R. L. de A., Silva, C. de F. O., Moura, C. A., Castro, R. N., … Lira, E. C. (2021). Hexane fraction from Brazilian Morus nigra leaves improved oral carbohydrate tolerance and inhibits α-amylase and α-glucosidase activities in diabetic mice. Natural Product Research, 35(22), 4785–4788. https://doi.org/10.1080/14786419.2020.1723087
Sim, L., Quezada-Calvillo, R., Sterchi, E. E., Nichols, B. L., & Rose, D. R. (2008). Human intestinal maltase-glucoamylase: Crystal structure of the N-terminal catalytic subunit and basis of inhibition and substrate specificity. Journal of Molecular Biology, 375(3), 782–792. https://doi.org/10.1016/j.jmb.2007.10.069
Srivastava, A., Yano, J., Hirozane, Y., Kefala, G., Gruswitz, F., Snell, G., Lane, W., Ivetac, A., Aertgeerts, K., Nguyen, J., Jennings, A., & Okada, K. (2014). High-resolution structure of the human GPR40 receptor bound to allosteric agonist TAK-875. Nature, 513(7516), 124–127. https://doi.org/10.1038/nature13494
Thomson, S. A., Banker, P., Bickett, D. M., Boucheron, J. A., Carter, H. L., Clancy, D. C., Cooper, J. P., Dickerson, S. H., Garrido, D. M., Nolte, R. T., Peat, A. J., Sheckler, L. R., Sparks, S. M., Tavares, F. X., Wang, L., Wang, T. Y., & Weiel, J. E. (2009). Anthranilimide based glycogen phosphorylase inhibitors for the treatment of type 2 diabetes. Part 3: X-ray crystallographic characterization, core and urea optimization and in vivo efficacy. Bioorganic and Medicinal Chemistry Letters, 19(4), 1177–1182. https://doi.org/10.1016/j.bmcl.2008.12.085v
Williams, L. K., Li, C., Withers, S. G., & Brayer, G. D. (2012). Order and disorder: Differential structural impacts of myricetin and ethyl caffeate on human amylase, an antidiabetic target. Journal of Medicinal Chemistry, 55(22), 10177–10186. https://doi.org/10.1021/jm301273u
Wu, J. X., Ding, D., Wang, M., Kang, Y., Zeng, X., & Chen, L. (2018). Ligand binding and conformational changes of SUR1 subunit in pancreatic ATP-sensitive potassium channels. Protein and Cell, 9(6), 553–567. https://doi.org/10.1007/s13238-018-0530-y
Yang, L., Zhao, J., Fan, S., Liao, J., Chen, Y., & Wang, Y. (2023). Effect of frost on the different metabolites of two mulberry (Morus nigra L. and Morus alba L.) leaves. Molecules, 28(12), 4718. https://doi.org/10.3390/molecules28124718
Zhou, Q. Y. J., Liao, X., Kuang, H. M., Li, J. Y., & Zhang, S. H. (2022). LC-MS metabolite profiling and the hypoglycemic activity of Morus alba L. extracts. Molecules, 27(17), 5360. https://doi.org/10.3390/molecules27175360v
