Kalisteginlerin Sükraz-İzomaltaz Enzim İnhibisyonunun İn-siliko Analizi

Yıl 2025, Cilt: 15 Sayı: 1, 60 - 72, 15.03.2025

Safinur Çelik

https://doi.org/10.31466/kfbd.1481022

Öz

Beslenme ile ilgili kronik hastalıklar dünya genelinde ve Türkiye’de hızla arttığı ve bu hastalıklar arasında prevalansı en yüksek olan hastalıkların diyabet ve obezite olduğu IDF (International Diabetes Federation) tarafından yapılan araştırmalarda ortaya konmuştur. Diyabet hastalarında önemli yan etkilere neden olan hiperglisemiyi baskılamak, diyet ile alınan karbohidrat sindirimini ve emilimini azaltmak veya yavaşlatmak etkili bir yaklaşımdır. Bu amaçla hiperglisemi tedavisinde sükraz-izomaltaz inhibitörü olan ilaçlar kullanılmaktadır. Ayrıca çalışmalarda bitkisel biyoaktif maddelerin sükraz-izomaltaz enzimini inhibe ettiğine dair bulgular bulunmaktadır. Kalisteginler doğal olarak bitkilerde bulunan alkaloidlerdir. Günlük diyetimizin bir parçası olan patates, patlıcan ve kırmızıbiberde kalistegin türlerinden A3, B2 ve B1’in bulunduğu bildirilmiştir. Bu türlerin sükraz-izomaltaz enzimi üzerine inhibisyon etkileri bu çalışmada in-siliko olarak incelenmiştir. LeDock programı in-siliko kenetlendirme için kullanılmıştır. Yapılan kenetlendirme işlemi pozitif kontrol olarak kotalanol kullanılarak doğrulanmıştır. Çalışma sonucunda A3, B2, B1 ve kotalanolün bağlanma enerjileri sırasıyla -5,40, -5,60, -5,86 ve -7,39 kkal/mol olarak program tarafından hesaplanmıştır. Bağlanma enerjilerinin inhibitör ve enzim arasında oluşan hidrojen bağ sayılarıyla doğru orantılı olduğu anlaşılmıştır. İnhibitörlerin taşıdığı hidroksil grubu sayısının enzimi inhibe etme kapasitesini arttırdığı sonucuna varılmıştır.

Anahtar Kelimeler

İn-siliko, Kenetleme, İnhibisyon, Sükraz-İzomaltaz, Kalistegin

In silico Analysis of Sucrase-Isomaltase Enzyme Inhibition by Calistegins

Öz

IDF (International Diabetes Federation) conducted research revealing that chronic diseases related to nutrition are increasing rapidly around the world including Turkey, and the diseases with the highest prevalence are diabetes and obesity. In order to suppress hyperglycemia, which causes significant side effects in diabetic patients, reducing or slowing down the digestion and absorption of dietary carbohydrates is an effective approach. For this purpose, sucrase-isomaltase inhibitor drugs are used in the treatment of hyperglycemia. Additionally, there are findings in studies that herbal bioactive substances inhibit the sucrase-isomaltase enzyme. It has been reported that potatoes, eggplants and red peppers, which are a part of our daily diet, contain calystegin types A3, B2 and B1. The inhibitory effects of these species on the sucrase-isomaltase enzyme were examined in silico for the first time in this study. The LeDock program was used for in-silico docking. The coupling process was confirmed using cotalanol as a positive control. The coupling process was confirmed using cotalanol as a positive control. As a result of the study, the binding energies of A3, B2, B1 and cotalanol were calculated by the program as -5.40, -5.60, -5.86 and -7.39 kcal/mol, respectively. It has been understood that binding energies are directly proportional to the number of hydrogen bonds formed between the inhibitor and the enzyme. It was concluded that the number of hydroxyl groups of the inhibitors increased the capacity to inhibit the enzyme.

Anahtar Kelimeler

In-silico, Docking, Inhibition, Sucrase-Isomaltase, Calystegin

Kaynakça

• Asano, N., Kato, A., Oseki, K., Kizu, H., & Matsui, K. (1995). Calystegins of Physalts alkekengi var. Francheti (Solanaceae): Structure Determination and their Glycosidase Inhibitory Activities. European Journal of Biochemistry, 229(2), 369–376. https://doi.org/10.1111/j.1432-1033.1995.0369k.x
• Baron, A. D. (1998). Postprandial hyperglycaemia and α-glucosidase inhibitors. Diabetes Research and Clinical Practice, 40(SUPPL.), 51–55. https://doi.org/10.1016/S0168-8227(98)00043-6
• Bourebaba, L., Saci, S., Touguit, D., Gali, L., Terkmane, S., Oukil, N., & Bedjou, F. (2016). Evaluation of antidiabetic effect of total calystegines extracted from Hyoscyamus albus. Biomedicine & Pharmacotherapy, 82, 337–344. https://doi.org/10.1016/J.BIOPHA.2016.05.011
• Deng, Y. X., Zhang, X. J., Shi, Q. Z., Chen, Y. S., Qiu, X. M., & Chen, B. (2012). Anti-hyperglycemic effects and mechanism of traditional Chinese medicine Huanglian Wan in streptozocin-induced diabetic rats. Journal of Ethnopharmacology, 144(2), 425–432. https://doi.org/10.1016/j.jep.2012.09.039
• Eberhardt, J., Santos-Martins, D., Tillack, A. F., & Forli, S. (2021). AutoDock Vina 1.2.0: New Docking Methods, Expanded Force Field, and Python Bindings. Journal of Chemical Information and Modeling, 61(8), 3891–3898. https://doi.org/10.1021/ACS.JCIM.1C00203/SUPPL_FILE/CI1C00203_SI_002.ZIP
• Ferreira, O. R., & Maruo, V. M. (2015). Toxicidade de Ipomoea setifera. Revista Cientifíca de Medicina Veterinária, 53(9), 1689–1699.
• Glerup, P., Grand, N., & Skydsgaard, M. (2013). The Use of Minipigs in Non-Clinical Research. In Haschek and Rousseaux’s Handbook of Toxicologic Pathology, Third Edition: Volume 1-3 (Vol. 1). Elsevier. https://doi.org/10.1016/B978-0-12-415759-0.00013-3
• Gong, L., Feng, D., Wang, T., Ren, Y., Liu, Y., & Wang, J. (2020). Inhibitors of α-amylase and α-glucosidase: Potential linkage for whole cereal foods on prevention of hyperglycemia. Food Science and Nutrition, 8(12), 6320–6337. https://doi.org/10.1002/fsn3.1987
• Hank, H., Szoke, É., Tóth, K., László, I., & Kursinszki, L. (2004). Investigation of tropane alkaloids in genetically transformed Atropa belladonna L. cultures. Chromatographia, 60(SUPPL.). https://doi.org/10.1365/s10337-004-0240-x
• IDF Diabetes Atlas | Tenth Edition. (2021). In International Diabetes Federation.
• Jocković, N., Fischer, W., Brandsch, M., Brandt, W., & Dräger, B. (2013). Inhibition of human intestinal α-glucosidases by calystegines. Journal of Agricultural and Food Chemistry, 61(23), 5550–5557. https://doi.org/10.1021/jf4010737
• Jokura, H., Watanabe, I., Umeda, M., Hase, T., & Shimotoyodome, A. (2015). Coffee polyphenol consumption improves postprandial hyperglycemia associated with impaired vascular endothelial function in healthy male adults. Nutrition Research, 35(10), 873–881. https://doi.org/10.1016/J.NUTRES.2015.07.005
• Jones, K., Eskandari, R., Naim, H. Y., Pinto, B. M., & Rose, D. R. (2012). Investigations of the structures and inhibitory properties of intestinal maltase glucoamylase and sucrase isomaltase. Journal of Pediatric Gastroenterology and Nutrition, 55(SUPPL.2). https://doi.org/10.1097/01.MPG.0000421403.34763.71
• Kato, A., Asano, N., Kizu, H., Matsui, K., Suzuki, S., & Arisawa, M. (1997). Calystegine alkaloids from Duboisia leichhardtii. Phytochemistry, 45(2), 425–429. https://doi.org/10.1016/S0031-9422(96)00865-5
• Kim, H. H., Kang, Y. R., Lee, J. Y., Chang, H. B., Lee, K. W., Apostolidis, E., & Kwon, Y. I. (2018). The postprandial anti-hyperglycemic effect of pyridoxine and its derivatives using in vitro and in vivo animal models. Nutrients, 10(3). https://doi.org/10.3390/nu10030285
• Kobayashi, M., Akaki, J., Ninomiya, K., Yoshikawa, M., Muraoka, O., Morikawa, T., & Odawara, M. (2021). Dose-Dependent Suppression of Postprandial Hyperglycemia and Improvement of Blood Glucose Parameters by Salacia chinensis Extract: Two Randomized, Double-Blind, Placebo-Controlled Studies. Journal Medicinal Food, 24(1), 10–17. https://doi.org/10.1089/JMF.2020.4751
• Lee, S. H., Park, M. H., Heo, S. J., Kang, S. M., Ko, S. C., Han, J. S., & Jeon, Y. J. (2010). Dieckol isolated from Ecklonia cava inhibits α-glucosidase and α-amylase in vitro and alleviates postprandial hyperglycemia in streptozotocin-induced diabetic mice. Food and Chemical Toxicology, 48(10), 2633–2637. https://doi.org/10.1016/j.fct.2010.06.032
• Meira, M., da Silva, E. P., David, J. M., & David, J. P. (2012). Review of the genus Ipomoea: traditional uses, chemistry and biological activities. Revista Brasileira de Farmacognosia, 22(3), 682–713. https://doi.org/10.1590/S0102-695X2012005000025
• Nejadhabibvash, F., Rahmani, F., & Jamei, R. (2012). Assessment of genetic diversity among Hyoscyamus genotypes based on ISSR markers. International Journal of Agriculture and Crop Sciences, 4(17), 1300–1306. www.ijagcs.com
• Oh, J., Jo, S. H., Kim, J. S., Ha, K. S., Lee, J. Y., Choi, H. Y., Yu, S. Y., Kwon, Y. I., & Kim, Y. C. (2015). Selected tea and tea pomace extracts inhibit intestinal α-glucosidase activity in vitro and postprandial hyperglycemia in vivo. International Journal of Molecular Sciences, 16(4), 8811–8825. https://doi.org/10.3390/IJMS16048811
• Pino-Gonzalez, M. S., Ona, N., & Romero-Carrasco, A. (2012). Advances in the synthesis of calystegines and related products and their biochemical properties. Mini Reviews in Medicinal Chemistry, 12(14), 1477–1484. https://doi.org/10.2174/138955712803832708
• Pistrosch, F., Natali, A., & Hanefeld, M. (2011). Is hyperglycemia a cardiovascular risk factor? Diabetes Care, 34(SUPPL. 2), 128. https://doi.org/10.2337/dc11-s207
• Sim, L., Willemsma, C., Mohan, S., Naim, H. Y., Pinto, B. M., & Rose, D. R. (2010). Structural basis for substrate selectivity in human maltase-glucoamylase and sucrase-isomaltase N-terminal domains. Journal of Biological Chemistry, 285(23), 17763–17770. https://doi.org/10.1074/jbc.M109.078980
• Tolmie, M., Bester, M. J., & Apostolides, Z. (2021). Inhibition of α-glucosidase and α-amylase by herbal compounds for the treatment of type 2 diabetes: A validation of in silico reverse docking with in vitro enzyme assays. Journal of Diabetes, 13(10), 779–791. https://doi.org/10.1111/1753-0407.13163
• Trott, O., & Olson, A. J. (2010). AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. Journal of Computational Chemistry, 31(2), 455–461. https://doi.org/10.1002/JCC.21334
• Türkiye İstatistik Kurumu. (2021). TÜİK Kurumsal. Bitkisel Üretim İstatistikleri, 2024. https://data.tuik.gov.tr/Bulten/Index?p=Bitkisel-Uretim-Istatistikleri-2024-53447
• Zhang, N., & Zhao, H. (2016). Enriching screening libraries with bioactive fragment space. Bioorganic & Medicinal Chemistry Letters, 26(15), 3594–3597. https://doi.org/10.1016/J.BMCL.2016.06.013