In Silico İnvestigating Scutellarin, Plantago Majör Flavonoid as an Alternative to Orlistat

Öz

The World Health Organisation (WHO) defines obesity as an abnormal or excessive accumulation of fat in the body that may impair health. It is stated that the best drug recommended to treat obesity is orlistat. In this study, the binding potential of Scutellarin, a Plantago major flavonoid that may be an alternative to orlistat, to the 5NN8 PDB coded receptor was investigated in silico in order to shed light on new drug designs. The inhibition potential of Scutellarin and Orlistat compounds on α-glucosidase enzymes that enable rapid absorption of complex carbohydrates by converting them into glucose was investigated using UCSF Chimera-1.17.3 and AutoDockTools-1.5.6 software. BIOVIA Discovery Studio software was used to visualise the results and elucidate the docking mechanisms. In this study, the results of the molecular docking study performed between the 5NN8 protein obtained from the protein data bank and the control compounds Orlistat and Scutellarinin; the binding score between 5NN8 and Orlistat was calculated as -6.0 kcal/mol, while the binding score between 5NN8 and Scutellarinin was calculated as -7.5 kcal/mol. The inhibitory activity of Scutellarin against α-glucosidase was evaluated in comparison with the standard inhibitor Orlistat. It was shown that the binding score of Scutellarin compound found by molecular docking study was -7.5 kcal/mol, which is better than Orlistat -6.0 kcal/mol. In addition, the pharmacological and toxicological properties of the studied compounds were studied in silico with the help of drug-likeness and ADMET analysis. ADMET study showed that Scutelleranin has a non-toxic structure. Although these results show that Scutellarin may have the potential to be an obesity inhibitor, it is clear that further in vivo and in vitro studies will be needed.

Anahtar Kelimeler

• Orlistat
• scutellarin
• plantago majör
• flavonoid
• İn-silico

Kaynakça

1. Abdullah, S., Iqbal, A., Ashok, A. K., Kaouche, F. C., Aslam, M., Hussain, S., . . . Ashraf, M. (2024). Anti-enzymatic and DNA docking studies of montelukast: A multifaceted molecular scaffold with in vitro investigations, molecular expression analysis and molecular dynamics simulations. Heliyon, 10(2).
2. Bayrakdar, A, . & Keleş, İ. (2024, 12-13 March 2024). Investigation of Chemical Reactivity of Plantago Major Flavonoids by HOMO-LUMO Molecular Orbital Analysis Method. Paper presented at the 4th International Conference on Innovative Academic Studies, Konya, Turkey.
3. Alpcan, A., & Durmaz, Ş. A. (2015). Çağımızın dev sorunu: çocukluk çağı obezitesi. Turkish Journal of Clinics and Laboratory, 6(1), 30-38.
4. Bayrakdar, A., Magudeeswaran, S., Manivannan, P., & Bangaru, S. (2024). Spectroscopic, DFT investigation and active site analysis of 2, 2-diphenyl-1, 3-propanediol against estrogen receptor EPR gamma. Research on Chemical Intermediates, 1-20.
5. Blüher, M. (2019). Obesity: global epidemiology and pathogenesis. Nature Reviews Endocrinology, 15(5), 288-298.
6. Boiko, A. S., Pozhidaev, I. V., Paderina, D. Z., Bocharova, A. V., Mednova, I. A., Fedorenko, O. Y., . . . Bokhan, N. A. (2021). Search for possible associations of fto gene polymorphic variants with metabolic syndrome, obesity and body mass index in schizophrenia patients. Pharmacogenomics and personalized medicine, 1123-1131.
7. Cengiz, M., Gür, B., Sezer, C. V., Cengiz, B. P., Gür, F., Bayrakdar, A., & Ayhancı, A. (2023). Alternations in interleukin-1β and nuclear factor kappa beta activity (NF-kB) in rat liver due to the co-exposure of Cadmium and Arsenic: Protective role of curcumin. Environmental Toxicology and Pharmacology, 102, 104218.
8. Cho, H.-W., Chung, W., Moon, S., Ryu, O.-H., Kim, M. K., & Kang, J. G. (2021). Effect of sarcopenia and body shape on cardiovascular disease according to obesity phenotypes. Diabetes & metabolism journal, 45(2), 209.

9. Daneschvar, H. L., Aronson, M. D., & Smetana, G. W. (2016). FDA-approved anti-obesity drugs in the United States. The American journal of medicine, 129(8), 879. e871-879. e876.
10. Emerenziani, S., Pier Luca Guarino, M., Trillo Asensio, L. M., Altomare, A., Ribolsi, M., Balestrieri, P., & Cicala, M. (2019). Role of overweight and obesity in gastrointestinal disease. Nutrients, 12(1), 111.
11. Hamedifar, H., Mohammadi‐Khanaposhtani, M., Sherafati, M., Noori, M., Moazam, A., Hosseini, S., . . . Erdogan, M. K. (2023). Design, synthesis, α‐glucosidase inhibition, pharmacokinetic, and cytotoxic studies of new indole‐carbohydrazide‐phenoxy‐N‐phenylacetamide derivatives. Archiv der Pharmazie, 356(6), 2200571.
12. Gombar, V. K., & Hall, S. D. (2013). Quantitative structure–activity relationship models of clinical pharmacokinetics: clearance and volume of distribution. Journal of chemical information and modeling, 53(4), 948-957.
13. Ince, N., Kaya, Ş., Yıldız, İ. E., Parlak, E., & Bayar, B. (2020). Use of complementary and alternative medicine in patients with chronic viral hepatitis in Turkey. Complementary therapies in medicine, 48, 102229.
14. Israili, Z. H. (2011). Advances in the treatment of type 2 diabetes mellitus. American journal of therapeutics, 18(2), 117-152.
15. İzol, E., & Yapici, İ. (2023, October 2023). EFFECT of α-GLUCOSIDASE and α-AMYLASE ENZYMES on DIABETES. Paper presented at the 6. Internatıonal Marmara Scıentıfıc Research And Innovatıon Congress, İstanbul- Turkey.
16. Keleş, İ. (2019). Ratlarda yüksek yağlı diyet ile indüklenen obezite oluşumu üzerine silymarin'in engelleyici etkisinin histopatolojik ve biyokimyasal olarak araştırılması. (Tüksek Lisans), Van Yüzüncü Yıl Üniversitesi, Van-Türkiye.
17. Kitadokoro, K., Tanaka, M., Hikima, T., Okuno, Y., Yamamoto, M., & Kamitani, S. (2020). Crystal structure of pathogenic Staphylococcus aureus lipase complex with the anti-obesity drug orlistat. Scientific reports, 10(1), 5469.
18. Koh, Y.-M., Jang, S.-W., & Ahn, T.-W. (2019). Anti-obesity effect of Yangkyuksanwha-tang in high-fat diet-induced obese mice. BMC complementary and alternative medicine, 19, 1-12.
19. Kotsis, V., Tsioufis, K., Antza, C., Seravalle, G., Coca, A., Sierra, C., . . . Redon, J. (2018). Obesity and cardiovascular risk: a call for action from the European Society of Hypertension Working Group of Obesity, Diabetes and the High-risk Patient and European Association for the Study of Obesity: part B: obesity-induced cardiovascular disease, early prevention strategies and future research directions. Journal of hypertension, 36(7), 1441-1455.
20. Kuang, M., Sheng, G., Hu, C., Lu, S., Peng, N., & Zou, Y. (2022). The value of combining the simple anthropometric obesity parameters, Body Mass Index (BMI) and a Body Shape Index (ABSI), to assess the risk of non-alcoholic fatty liver disease. Lipids in health and disease, 21(1), 104.
21. Lankatillake, C., Luo, S., Flavel, M., Lenon, G. B., Gill, H., Huynh, T., & Dias, D. A. (2021). Screening natural product extracts for potential enzyme inhibitors: Protocols, and the standardisation of the usage of blanks in α-amylase, α-glucosidase and lipase assays. Plant Methods, 17, 1-19.
22. Lipinski, C. A., Lombardo, F., Dominy, B. W., & Feeney, P. J. (1997). Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Advanced drug delivery reviews, 23(1-3), 3-25.
23. Luo, S., Gill, H., Dias, D. A., Li, M., Hung, A., Nguyen, L. T., & Lenon, G. B. (2019). The inhibitory effects of an eight-herb formula (RCM-107) on pancreatic lipase: enzymatic, HPTLC profiling and in silico approaches. Heliyon, 5(9).
24. Mullard, A. (2018). Re-assessing the rule of 5, two decades on. Nature reviews. Drug discovery, 17(11), 777.
25. Newman, D. J., & Cragg, G. M. (2016). Natural products as sources of new drugs from 1981 to 2014. Journal of natural products, 79(3), 629-661.
26. Noor, Z. I., Ahmed, D., Rehman, H. M., Qamar, M. T., Froeyen, M., Ahmad, S., & Mirza, M. U. (2019). In vitro antidiabetic, anti-obesity and antioxidant analysis of Ocimum basilicum aerial biomass and in silico molecular docking simulations with alpha-amylase and lipase enzymes. Biology, 8(4), 92.
27. Ogunyemi, O. M., Gyebi, G. A., Ibrahim, I. M., Esan, A. M., Olaiya, C. O., Soliman, M. M., & Batiha, G. E.-S. (2023). Identification of promising multi-targeting inhibitors of obesity from Vernonia amygdalina through computational analysis. Molecular Diversity, 27(1), 1-25.
28. 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.
29. 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.
30. Qi, X. (2018). Review of the clinical effect of orlistat. Paper presented at the IOP Conference Series: Materials Science and Engineering.
31. Sarkar, P., Alheety, M. A., & Srivastava, V. (2023, February). Molecular Docking and ADMET Study of Spice‐Derived Potential Phytochemicals against Human DNA Topoisomerase III Alpha. In Macromolecular Symposia (Vol. 407, No. 1, p. 2200108).
32. Sivashanmugam, T., Muthukrishnan, S., Umamaheswari, M., Asokkumar, K., Subhadradevi, V., Jagannath, P., & Madeswaran, A. (2013). Discovery of potential cholesterol esterase inhibitors using in silico docking studies. ||| Bangladesh Journal of Pharmacology, 8(3), 223-229.
33. Tak, Y. J., & Lee, S. Y. (2021). Anti-obesity drugs: long-term efficacy and safety: an updated review. The world journal of men's health, 39(2), 208.
34. Uğur, K., Şener, Y. S., & Özkan, Y. (2016). Obezitenin Tanımı, Epidemiyolojisi ve Klinik Önemi. Türkiye Klinikleri Kozmetik Dermatoloji Özel Dergisi, 9(2).
35. Uyar , A., & Esim, E. (2018). Yüksek Yağlı Diyet ile Beslenen Ratlarda Mate (Ilex paraguariensis) Çayının Obeziteyi Önleyici Etkisinin Histopatolojik ve Biyokimyasal Olarak Araştırılması. Harran Üniversitesi Veteriner Fakültesi Dergisi, 7(2), 154-161.
36. Van, L. V., Pham, E. C., Nguyen, C. V., Duong, N. T. N., Le Thi, T. V., & Truong, T. N. (2022). In vitro and in vivo antidiabetic activity, isolation of flavonoids, and in silico molecular docking of stem extract of Merremia tridentata (L.). Biomedicine & Pharmacotherapy, 146, 112611.
37. Vardhan, S., & Sahoo, S. K. (2020). In silico ADMET and molecular docking study on searching potential inhibitors from limonoids and triterpenoids for COVID-19. Computers in biology and medicine, 124, 103936.
38. Wang, J., Lu, S., Sheng, R., Fan, J., Wu, W., & Guo, R. (2020). Structure-activity relationships of natural and synthetic indole-derived scaffolds as α-glucosidase inhibitors: a mini-review. Mini Reviews in Medicinal Chemistry, 20(17), 1791-1818.
39. Zhakipbekov, K., Turgumbayeva, A., Issayeva, R., Kipchakbayeva, A., Kadyrbayeva, G., Tleubayeva, M., . . . Serikbayeva, E. (2023).
40. Antimicrobial and Other Biomedical Properties of Extracts from Plantago major, Plantaginaceae. Pharmaceuticals, 16(8), 1092.