ALZHEİMER HASTALIĞINDA İLAÇ ADAYI OLARAK PROTOBERBERİN ALKALOİTLERİNİN GLİKOJEN SENTAZ KİNAZ 3β İLE MOLEKÜLER BAĞLANMA PROFİLLERİ

Yıl 2018, Cilt: 42 Sayı: 3, 1 - 12, 30.09.2018

Gozde Yalcın , İlkay Yıldız

Öz

Amaç: Berberin, palmatin, yatrorrizin, kolumbamin, magnoflorin gibi protoberberin alkaloitlerin nörodejeneratif hastalıklardan koruduğu deneysel olarak tespit edilmiş olmasına rağmen; buna yol açan mekanizma tam olarak açıklanamamıştır. Bu çalışmada, bu alkaloitlerin GSK-3β ile bağlanma ve etki mekanizmalarını açığa kavuşturmak hedeflenmiştir.

Gereç ve Yöntem: Glikojen Sentaz Kinaz 3β (GSK-3β) Alzheimer Hastalığına (AD) ait süreçlerde vazgeçilmez öneme sahip bir serin/treonin kinazdır. Alzheimer Hastalığı tau hiperfosforilasyonu ve amiloid β (Aβ) proteinlerin birikimi gibi nöropatolojik belirteçler göstermektedir. Aβ proteinleri Amiloid Öncül Protein (APP)’nin sekanssal kesimi ile meydana gelmektedir. Son dönemlerdeki çalışmalar GSK-3β inhibisyonunun APP kesiminde gerilemeye yol açtığını ortaya koymuştur. Böylece Aβ birikimi bu proses ile önlenmektedir. GSK-3β inhibisyonunun terapötik önemi nedeniyle Bilim insanları için önemli bir hedef haline gelmiştir. Alkaloidler çeşitli yapılardaki bitkiler gibi pek çok organizma tarafından üretilen sekonder metabolitlerdir. Alkaloitlerin GSK-3β ile bağlanma ve etki mekanizmalarını açığa kavuşturmak amacıyla; bu doğal ürünlerle, Discovery Studio 3.5 Client programına ait CDOCKER modulü kullanılarak moleküler doking çalışmaları yürütülmüştür. GSK-3β ile ligandlar arasındaki bağlanma mekanizması Hidrojen ve π bağları vasıtasıyla tespit edilmiştir.

Sonuç ve Tartışma: Dikkat çekici özellikleriyle bazı protoberberin alkaloitlerinin GSK-3β inhibisyonu üzerindeki etkileri incelenmiştir. Moleküller -7.0 kcal/mol’den küçük bir bağlanma afinitesi göstermiştir. En iyi doking sonuçları magnoflorinden elde edilmiştir. Diğer protoberberin alkaloitlerinin aksine magnoflorin daha kompakt bir yapıya sahiptir. Bu özelliğinin reseptöre bağlanma kapasitesinin arttırılmasında etkili olabileceği düşünülmüştür.

Anahtar Kelimeler

alzheimer hastalığı, glikojen sentaz kinaz 3β, moleküler doking, protoberberin alkaloitleri

MOLECULAR BINDING PROFILE OF PROTOBERBERINE ALKALOIDS ON GLYCOGEN SYNTHASE KINASE 3β AS a DRUG CANDIDATE FOR ALZHEIMER’S DISEASES

Öz

Objective: Protoberberine alkaloids such as berberine, palmatine, jatrorrhizine, columbamine, magnoflorine were found to prevent a progressive neurodegenerative disorder as experimentally, the mechanisms of them are not absolutely clear. In this study, we have aimed to elucidate the binding and affect mechanism of these alkaloids on the GSK-3β.

Material and Method: Glycogen Synthase Kinase 3β (GSK-3β) is a serine/threonine kinase which has essential roles in Alzheimer’s Diseases (AD) processes. AD shows neuropathological markers as tau hyperphosphorylation and accumulation of amyloid β (Aβ) proteins. Aβ proteins are generated from sequential cleavages of amyloid precursor protein (APP). Recent studies show that inhibition of GSK-3β causes to decrease in the cleavage of APP. Thus the accumulation of Aβ was prevented by this process. Due to the therapeutic benefit of the inhibition of GSK-3β it has been a favoured target for scientists.

Alkaloids are secondary metabolites which are produced by a large variety of organisms as plants with diverse structures. To explain the binding and the effect mechanism of GSK-3β, molecular docking studies were applied on these natural products by using CDOCKER module of Discovery Studio 3.5 Client. Binding mechanism was identified by Hydrogen, π bindings between ligands and GSK-3β.

Result and Discussion: It has established that some protoberberine alkaloids with attractive properties about inhibition of GSK-3β. The molecules exhibited <-7.0 kcal/mol binding affinity values. Best docked results were detected with magnoflorine. In contrast with the other protoberberine alkaloids, magnoflorine has a compact structure. It could be more effective on binding affinity to receptor due to this reason.

Anahtar Kelimeler

alzheimer’s disease, glycogen synthase kinase 3β, molecular docking, protoberberine alkaloid

Kaynakça

• National Institute of Aging. (2016). Alzheimer’s Disease Fact Sheet. National Library of Medicine, Retrieved April 12, 2018, from https://www.nia.nih.gov/health/alzheimers-disease-fact-sheet
• Namrata, C. (2012). Case Study-Alzheimer’s Disease. Biochemistry for Medics. Retrieved April 12, 2018, from http://www.namrata.co/case-study-alzheimer-disease/
• Zhang, Y., Thompson, R., Zhang, H., Xu, H. (2011). APP processing in Alzheimer’s disease. Mol. Brain, 4, 3. Retrieved April 12, 2018, from http://www.molecularbrain.com/content/4/1/3
• Ly, P.T.T., Wu,Y., Zou, H., Wang, R., Zhou, W., Kinoshita, A., Zhang, M., Yang, Y., Cai, F., Woodgett, J., Song, W. (2013). Inhibition of GSK3β-mediated BACE1 expression reduces Alzheimer-associated phenotypes. Journal of Clinical Investigation, 123, 224-235.
• Singh, S., Kushwah, A.S., Singh, R., Farswan, M., Kaur, R. (2012). Current therapeutic strategy in Alzheimer’s disease. European Review for Medical and Pharmacological Sciences, 16, 1651-1664.
• Grycová, L., Dostál, J., Marek, R. (2007). Quaternary protoberberine alkaloids. Phytochemistry, 68(2), 150-175.
• Kamath, S., Skeels, M., Pai, A. (2009). Significant differences in alkaloid content of Coptis chinensis (Huanglian), from its related American species. Chinese Medical Journal, 4, 17.
• Sarma, N.D., Koul, S., Khosa, R.L. (2009). Alkaloids from Tinospora cordifolia miers. Journal of Pharmaceutical Sciences and Research, 1(1), 26-27.
• He, S.M., Liang, Y.L., Cong, K., Chen, G., Zhao, X., Zhao, Q.M., Zhang, J.J., Wang, X., Dong, Y., Yang, J.L., Zhang, G.H., Qian, Z.L., Fan, W., Yang, S.C. (2018) Identification and Characterization of Genes Involved in Benzylisoquinoline Alkaloid Biosynthesis in Coptis Species. Frontiers in Plant Science, 9, 1-13.
• Inbaraj, J.J., Kukielczak, B.M., Bilski, P., Sandvik, S.L., Chignell, C.F. (2011). Photochemistry and Photocytotoxicity of Alkaloids from Goldenseal ( Hydrastis canadensis L. ). Chemical Research in Toxicology, 14(11), 1529-1534.
• Sonmezdag, A.S., Kelebek, H., Selli, S. (2018). Volatile and key odourant compounds of Turkish Berberis crataegina fruit using GC-MS-Olfactometry. Natural Product Research, 32(7), 777-781.
• Leitao da-Cunha, E.V., Fechine, I.M., Guedes, D.N., Barbosa-Filho, J.M., Sobral da Silva, M. (2005). Protoberberine Alkaloids. The Alkaloids: Chemistry and Biology, 62, 1-75.
• Cai, Z., Wang, C., Yang, W. (2016). Role of berberine in Alzheimer’s disease. Neuropsychiatric Disease and Treatment, 12, 2509-2520.
• Wu, G., Robertson, D.H., Brooks, C.L., Vieth, M. (2003). Detailed analysis of grid-based molecular docking: A case study of CDOCKER - A CHARMm based MD docking program. Journal of Computational Chemistry, 24, 1549-1562.
• Accelrys Software Inc. Discovery Studio 3.5 Client. San Diego: Accelrys Inc.; 2012.
• Dajani, R., Fraser, E., Roe, S.M., Young, N., Good, V., Dale, T.C., Pearl, L.H. (2001). Crystal structure of glycogen synthase kinase 3 beta: structural basis for phosphate-primed substrate specificity and autoinhibition. Cell, 105, 721-732.
• Kukula-Koch, W., Kruk-Słomka, M., Stępnik, K., Szalak, R., Biała, G. (2017). The evaluation of pro-cognitive and antiamnestic properties of berberine and magnoflorine isolated from barberry species by Centrifugal Partition Chromatography (CPC), in relation to QSAR modelling. International Journal of Molecular Sciences, 18, 2511.