Özet
A total of 14.8 million people in Turkey (27.1%) use tobacco products. Nicotine dependence is the first cause of continued smoking behavior and overall failure of treatment interventions. Nicotine, an alkaloid derived from the leaves of the Nicotiana tabacum plant, is a very easily absorbed substance and is easily and rapidly absorbed by the lungs, mouth, nose, skin. Nicotine is the main cause of cigarette dependence.
The nicotinic acetylcholine receptor (nAChR) is an ion channel receptor, which is activated by acetylcholine and nicotine which is the main component of tobacco dependence. To date, 17 nACh receptor subunits have been identified, including muscarinic (α1, β1, γ, δ and ε) and neuronal (α2-α10 and β2-β4). The most widely distributed nAChR subunits in the central nervous system are α4β2 (~ 90%) and α7 (~ 10%) subunits. The α4β2 subunit is the target structure of smoking cessation drugs.
Although there are several experimental studies (in vivo and in vitro) that some phytochemicals (camphor, menton, menthol, carvacrol, thymoquinone, flavonoids, etc.) in some plants (avena sativa, hypericum perforatum, lavandula stoechas, lobelia inflata, nigella sativa, piper nigrum) are smoking cessation features, there are no any studies with nAChR (nicotinic acetylcholine receptor) including binding properties and energy.
Our aim is to investigate how some phytochemicals (camphor, menton, menthol, carvacrol, thymoquinone, flavonoids, etc.) in some plants (avena sativa, hypericum perforatum, lavandula stoechas, lobelia inflata, nigella sativa, piper nigrum) interact with nAChR as an antagonist by using Docking program Autodock Vina.
In the first part of the study, the validation of the AutoDock Vina program was performed for AChBP (acetylcholine binding protein) 1UW6 and 2BYR. As a result of calculation, RMSD values for 1UW6 and 2BYR were found 1.3 and 1.6 Å respectively. Due to RMSD value is less than 2 Å, AutoDock Vina has been determined to be suitable for the selected system.
In the second step, geometry optimization of phytochemicals in lavandula stoechas, avena sativa, piper nigrum, lobelia inflata, hypericum perforatum and nigella sativa were performed by DFT/B3LYP/6-31G(d,p) and the binding of phytochemicals to the active site of AChBP was analyzed by using the AutoDock Vina program. İt was found that miquelianin has the highest antagonist activity.
In the last part of the study, virtual ligand screening study was performed for 506 compounds in ZINC15 database. Our calculation results showed that the first 20 structures showing the best binding affinity would be promising candidates.
As a result of the research carried out in this thesis, the obtained data will contribute to the design of new candidate antagonists which may be effective as nAChR antagonists.
Künye
KAYNAKLAR
[1] Billen, B., Spurny, R., Brams, M., Van, Elk R., Valera-Kummer, S., Yakel, JL., Voets, T., Bertrand, D., Smit, AB., Ulens, C., Molecular actions of smoking cessation drugs at α4β2 nicotinic receptors defined in crystal structures of a homologous binding protein, Proceedings of the National Academy of Sciences of the United States of America, 109(23), 9173-9178, 2012.
[2] Angioni, A., Barra, A., Coroneo, V., Dessi, S., Cabras, P., Chemical composition, seasonal variability, and antifungal activity of Lavandula stoechas L. ssp. stoechas essential oils from stem/leaves and flowers, Journal of Agricultural and Food Chemistry, 54(12), 4364-4370, 2006
[3] Kim Kuk, H., Kim Kyong, T., Nam Hong, G., Park Deok, H., Park Tae, J., Antagonists for nicotinic acetylcholine receptor, which are containing borneol or camphor as an active ingredient, Genomine, Inc., Pohang University Of Science And Technology, Patent NO: WO2001058436 A1, 2001.
[4] Silvana, L., Martin, C.M., K.Michael, C., James, L.K., Andrew, H., David D. L., Jill, M.M., A Phase II study of St. John’s Wort for smoking cessation, Complementary Therapies in Medicine, 14, 175—184, 2006.
[5] Amit S., Jon, O.E., Kavita, P., Ivana, T.C., Brent, B., Darrell, R.S., A Randomized Clinical Trial of St. John’s Wort for Smoking Cessation, The Journal of Alternative and Complementary Medicine, 16(7), 761-767, 2010.
[6] Yorgancıoğlu, A., Esen A., Sigara bağımlılığı ve hekimler, Toraks dergisi,1, 90-95, 2000.
[7] Küresel yetişkin tütün araştırması Türkiye 2012, Sağlık Bakanlığı yayın no:948, Anıl Matbaa, Ankara, 2-4, 2014.
[8] Bilir, N. ve ark., Tütün ve Alkol Piyayası Düzenleme Kurulu (TAPDK), http://www.tapdk.gov.tr/tr/piyasa-duzenlemeleri/tutun-ve-alkol-kontrolu/tutun-mamulleri-ve-saglik.aspx, (Nisan, 2008).
[9] Behr, J., Nowak, D., Tobacco smoke and respiratory disease. In: D’Amato G, Holgate ST; eds. The Impact of Air Pollution on Respiratory Health, ERS Journals Ltd. European Respiratory Journals, 21, 161-179, 2002.
[10] Elbek, O., Kılınç, O., Aytemur, Z.A., Akyıldız, L., Küçük, Ç.U., Özge, C., Sağlam, L., Bostan, P., Dağlı, E., Türkiye’de Tütün Kontrolü, Turk Toraks Dergisi, 1-10, 2014.
[11] Karlıkaya, C., Öztuna, F., Solak, Z.A., Özkan M., Örsel O., Tütün kontrolü, Toraks Dergisi, 7(1), 51-64, 2006.
[12] Patrick, G.L., An Introduction to Medicinal Chemistry, 5.Baskı, Oxford University Yayıncılık, 42-56, 2013.
[13] Akay, A., N.Ceren, Turanlıgil, S., Uyanıkgil, Y., İyon Kanalları ve Epilepsi Patojenezindeki Rolleri, Arşiv Kaynak Tarama Dergisi, 19, 72, 2010.
[14] Edink, E., Structure-based design of AChBP ligands, new insights and applications, Doktora Tezi, Vrije University Faculty of Sciences, Amsterdam, 2011.
[15] Brejc, K., et al. Crystal structure of an ACh-binding protein reveals the ligand-binding domain of nicotinic receptors, Nature, 411, 269-76, 2001.
[16] Arias, H.R., Molecular interactions between ligands and nicotinic acetylcholine receptors revealed by studies with acetylcholine binding proteins, Journal of Thermodynamics & Catalysis, 3(4), 1-7, 2012.
[17] Sharples, C.G.V., Wonnacott, S., Neuronal Nicotinic Receptors, Tocris Reviews, 19, 2001.
[18] Unwin, N., Refined Structure of the Nicotinic Acetylcholine Receptor at 4A Resolution, Journal of Molecular Biology, 346(4), 967, 2005.
[19] Unwin, N., Fujiyoshi, Y., Gating Movement of Acetylcholine Receptor Caught by Plunge-Freezing, Journal of Molecular Biology, 422, 617, 2012.
[20] Wonnacott S., Jacques B., Nicotinic ACh Receptors, Tocris Reviews, 28, 2007.
[21] Daly, J.W., Nicotinic Agonists, Antagonists, and Modulators From Natural Sources, Cellular and Molecular Neurobiology, 25 (3-4), 513-552, 2005.
[22] Prakash, R., Claire, A.H., René van Elk, August, B.S., Timothy, G., Titia, K.S., Structural Characterization of Binding Mode of Smoking Cessation Drugs to Nicotinic Acetylcholine Receptors through Study of Ligand Complexes with Acetylcholine-binding Protein, The Journal of Biological Chemistry, 287 (28), 23283-23293, 2012.
[23] Etter, J.F., Cytisine for smoking cessation: A literature review and a meta-analysis, Archives of Internal Medicine, 166, 1553-1559, 2006.
[24] Crooks, P.A., Bardo, M.T., Dwoskin, L.P., Nicotinic Receptor Antagonists as Treatments for Nicotine Abuse, Advances in Pharmacology, 69, 513-551, 2014.
[25] Ingrid, B., Becky, W., Douglas, R.S., Tony, P.G., Mecamylamine – a nicotinic acetylcholine receptor antagonist with potential for the treatment of neuropsychiatric disorders, Expert opinion on Pharmacotherapy, 10 (16), 2709-2721, 2009.
[26] Kitikannakorn, N., Chaiyakunapruk, N., Nimpitakpong, P., Dilokthornsakul, P., Meepoog, E., Kerdpeng, W., An overview of the evidences of herbals for smoking cessation, Complementary Therapies in Medicine, 21, 557-564, 2013.
[27] Barnes, J., Anderson, L.A., Phillipson, J.D., St John’s worth (Hypericum perforatum L.): a review of its chemistry, pharmacology and clinical properties, Journal of Pharmacy and Pharmacology, 53, 583-600, 2001.
[28] Butterweck, V., Schmidt, M., St. John’s wort: Role of active compounds for its mechanism of action and efficacy, Wiener Medizinische Wochenschrift, 157 (13-14), 356–361, 2007.
[29] Zou, Y., Lu, Y., Wei, D., Antioxidant activity of a flavonoid-rich extract of Hypericum perforatum L. in vitro, Journal of Agricultural and Food Chemistry, 52, 5032-5039, 2004.
[30] Wenzig, E., Kunert, O., Ferreira, D., Schmid, M., Schuhly, W., Bauer, R., Hiermann, A., Flavonolignans from Avena sativa, Journal of Natural Products, 68 (2), 289-292, 2005.
[31] Schmidt, K., Geckeler, K., Pharmacotherapy with avena sativa - a double blind study, International Journal of Clinical Pharmacology and Biopharmacy, 14(3), 214-216, 1976.
[32] Dimberg, L.H., Gisse´n, C., Nilsson, J., Phenolic Compounds in Oat Grains(Avena sativa L.) Grown in Conventional and Organic Systems, Ambio, 34 (4-5), 331-337, 2005.
[33] Felpin, F.X., Lebreton, J., History, chemistry and biology of alkaloids from Lobelia inflata, Tetrahedron , 60, 10127–10153, 2004.
[34] Stead, L.F., Hughes, J.R., Lobeline for smoking cessation, Cochrane Database of Systematic Reviews, 2, Art. No.:CD000124, DOI:10.1002/14651858.CD000124.pub2, 2012.
[35] Zuzartea, M., Goncalves, M.J., Cavaleiroa, C., Cruz, M.T., Benzarti A., Marongiu, B., Maxia, A., Piras, A., Salgueiroa, L., Antifungal and anti-inflammatory potential of Lavandula stoechas and Thymus herba-barona essential oils, Industrial Crops and Products, 44, 97-103, 2013.
[36] Ahmad, N., Fazal, H., Abbasi, B.H., Farooq, S., Mohammad Ali, Mubarak, A.K., Biological role of Piper nigrum L. (Black pepper): A Review, Asian Pacific Journal of Tropical Biomedicine, 1945-1953, 2012.
[37] Rose, J.E., Behm, F.M., Inhalation of vaporfrom black pepper extract reduces smoking withdrawal symptoms, Drug Alcohol Dependence, 34 (3), 225-229, 1994.
[38] Ahmad, A., Husain, A., Mujeeb, M., Alam Khan, S., Najmi, A.K., Sidduque, N.A., Damanhouri, Z.A., Anwar, F., A review of therapeutic potential of Nagilla sativa: A miracle herb, Asian Pacific Journal of Tropical Biomedicine, 3 (5), 337-352, 2013.
[39] Hosseinzadeh, H., Parvardeh, S., Masoudi, A., Moghimi, M., Mahboobifard, F., Attenuation of morphine tolerance and dependence by thymoquinone in mice, Avicenna Journal of Phytomedicine, 6 (1), 55-66, 2016.
[40] Alten, O., HIV-1 Glikoprotein 41 Molekülünün Aktif Bölgesinin Substrat- Bağlayıcı Alanının Moeküler Kenetlenme Yöntemiyle Araştırılması, Yüksek Lisans Tezi, Hacettepe Üniversitesi Fen Bilimleri Enstitüsü, Ankara, 2011.
[41] Ülgen, O., Trombin İnhibitörlerinin Moleküler Modelleme Çalışmaları, Yüksek Lisans Tezi, Hacettepe Üniversitesi Fen Bilimleri Enstitüsü, Ankara, 2012.
[42] http://autodock.scripps.edu/faqs-help/faq/how-autodock-4-converts-binding-energy-kcal-mol-into-ki (Aralık, 2015).
[43] Walters, W.P., Stahl, M.T., Murcko, M., Virtual screening-an overview, Drug Discovery Today, 3, 160-178, 1998.
[44] Davis, A.M., Teague, S.J., Kleywegt, G.J., Application and limitations of x-ray crystallographic data in structure-based ligand and drug design, Angewandte Chemie International Edition, 42, 2718-2736, 2003.
[45] Yang, Z., Lasker, K., Schneidman-Duhovny, D., Webb, B., Huang, C.C., Pettersen, E.F., Goddard, T.D., Meng E.C., Sali, A., Ferrin, T.E., UCSF Chimera, MODELLER, and IMP: An integrated modeling system, Journal of Structural Biology 179 (3), 269–278, 2012.
[46] Trott, O., Olson, A.J., AutoDock Vina: Improving the Speed and Accuracy of Docking with a New Scoring Function, Efficient Optimization, and Multithreading, Journal of Computational Chemistry, 31, 445-461, 2010.
[47] https://bidb.metu.edu.tr/380-gaussian-yazilimi (Mart, 2014).
[48] Zhenjiang Li, Honggui Wan, Yuhu Shi, Pingkai Ouyang, Personal Experience with Four Kinds of Chemical Structure Drawing Software: Review on ChemDraw, ChemWindow, ISIS/Draw, and ChemSketch, Journal of Chemical Information and Computer Sciences, 44, 1886-1890, 2004.
[49] http://pubchem.ncbi.nlm.nih.gov/ (Ocak, 2014).
[50] http://www.gaussian.com/g tech/ g ur/ u newzmat.htm (Ocak, 2014).
[51] http://www.rcsb.org/pdb/home/home.do (Aralık, 2013).
[52] https://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl?pdbcode=index.html (Ocak, 2018)
[53] Hansen, S.B., Sulzenbacher, G., Huxford, T., Marchot, P., Taylor, P., Bourne, Y., Structures of Aplysia AChBP complexes with nicotinic agonists and antagonists reveal distinctive binding interfaces and conformations, The EMBO Journal , 24, 3635–3646, 2005.
