Studi HKSA Senyawa Turunan 4-(3-nitrophenyl)-thyazol-2-ylhidrazone sebagai Inhibitor Monoamin Oksidase B
DOI:
https://doi.org/10.30595/pharmacy.v19i1.8780Keywords:
4-(3-nitrophenyl)-thiazol-2-ylhydrazone, inhibitor MAO-B, monoamin oksidase B, penyakit ParkinsonAbstract
Penyakit Parkinson adalah penyakit yang prevalensinya terus meningkat seiring peningkatan usia harapan hidup. Penemuan obat baru yang memiliki aktivitas lebih kuat dengan resiko efek samping yang lebih rendah masih menjadi tantangan tersendiri. Senyawa turunan 4-(3-nitrophenyl)-thiazol-2-ylhydrazone diketahui aktif sebagai inhibitor monoamin oxidase B (MAO-B). MAO-B merupakan target kerja penting dalam pengobatan Parkinson. Penelitian ini dilakukan untuk mendapat senyawa turunan baru yang diprediksi memiliki aktivitas lebih baik sebagai inhibitor MAO-B. 34 senyawa turunan 4-(3-nitrophenyl)-thiazol-2-ylhydrazone dipilih sebagai training set dan test set. Metode Hansch digunakan dalam studi ini. Model HKSA yang valid selanjutnya digunakan sebagai acuan desain senyawa turunan baru dan memprediksi aktivitasnya. Studi dilanjutkan dengan penambatan molekul untuk melihat interaksi dan afinitas senyawa baru pada enzim target tersebut. Studi HKSA ini melibatkan deskriptor 1 dan 2 dimensi. Model HKSA yang valid adalah [pIC50]Pred = (2,210120) +(0,208611xLog_S) +(-0,024341xMW ) + (-0,000002xE_Potential) +(0,237454xRMS) +(-0,012968xE_termal). Kriteria statistik pada model tersebut adalah R=0,967; R2=0,949; Fhitung/Ftabel= 25,627; dan q2 = 0,869. Berdasarkan model HKSA tersebut dihasilkan 17 senyawa turunan baru yang diprediksi lebih aktif dibandingkan senyawa dalam training set dan test set. 8 senyawa baru diprediksi memberikan afinitas yang lebih baik pada MAO-B berdasarkan studi penambatan molekul, yaitu: SB1, SB9, SB11, SB12, SB14, SB15, SB17 dan SB18.
References
Arba M, Ruslin R, Nursan N, Maulidiyah M, Tjahjono DH. 2018. Hubungan Kuantitatif Struktur-Aktivitas (HKSA) dan Penambatan Molekul Senyawa Turunan Benzamida sebagai Inhibitor Alosterik Mitogen Enhanced Kinase (MEK). Jurnal Kimia VALENSI. 4(1): 42-51. https://doi.org/10.15408/jkv.v4i1.7454
Balestrino R, Schapira AHV. 2020. Parkinson disease. European Journal of Neurology. 27(1): 27-42. https://doi.org/10.1111/ene.14108
Bendsøe MP, Ben-Tal A, Zowe J. 1994. Optimization methods for truss geometry and topology design. Structural Optimization. 7: 141-159. https://doi.org/10.1007/BF01742459
Dezsi L, Vecsei L. 2017. Monoamine Oxidase B Inhibitors in Parkinson’s Disease. CNS & Neurological Disorders - Drug Targets. 16(4): 425-439. https://doi.org/10.2174/ 1871527316666170124165222
Finberg JPM, Rabey JM. 2016. Inhibitors of MAO-A and MAO-B in psychiatry and neurology. Frontiers in Pharmacology. 7:340. https://doi.org/10.3389/fphar.2016.00340
Fowler JS, Volkow ND, Wang GJ, Logan J, Pappas N, Shea C, MacGregor R. 1997. Age-related increases in brain monoamine oxidase B in living healthy human subjects. Neurobiology of Aging. 18(4): 431-435. ttps://doi.org/10.1016/S0197-4580(97)00037-7
Li S, Lv X, Cheng K, Tian Y, Huang X, Kong H, Duan Y, Han J, Liao C, Xie Z. 2019. Discovery of novel 2,3-dihydro-1H-inden-1-amine derivatives as selective monoamine oxidase B inhibitors. Bioorganic and Medicinal Chemistry Letters. 29(9): 1090-1093.https://doi.org/10.1016/j.bmcl.2019.02.030
Morris GM, Goodsell DS, Halliday RS, Huey R, Hart WE, Belew RK, Olson AJ. 1998. Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function. Journal of Computational Chemistry. 19(14): 1639-1662. https://doi.org/10.1002/(SICI)1096-987X(19981115)19:14<1639::AID-JCC10>3.0.CO;2-B
Picard RR, Cook RD. 1984. Cross-validation of regression models. Journal of the American Statistical Association. 79: 387. https://doi.org/10.1080/01621459.1984.10478083
Prachayasittikul V, Pingaew R, Worachartcheewan A, Nantasenamat C, Prachayasittikul S, Ruchirawat S, Prachayasittikul V. 2014. Synthesis, anticancer activity and QSAR study of 1,4-naphthoquinone derivatives. European Journal of Medicinal Chemistry. 84: 247-263. https://doi.org/10.1016/j.ejmech.2014.07.024
Qhobosheane MA, Legoabe LJ, Petzer A, Petzer JP. 2019. The monoamine oxidase inhibition properties of C6-mono- and N3/C6-disubstituted derivatives of 4(3H)-quinazolinone. Bioorganic Chemistry, 85: 60–65. https://doi.org/10.1016/j.bioorg.2018.12.030
Ramsay RR. 2016. Molecular aspects of monoamine oxidase B. Progress in Neuro-Psychopharmacology and Biological Psychiatry. 69: 81-89. https://doi.org/10.1016/j.pnpbp.2016.02.005
Reis J, Manzella N, Cagide F, Mialet-Perez J, Uriarte E, Parini A, Borges F, Binda C. 2018. Tight-binding inhibition of human monoamine oxidase B by chromone analogs: A kinetic, crystallographic, and biological analysis. Journal of Medicinal Chemistry. 61(9): 4203-4212.https://doi.org/10.1021/acs.jmedchem.8b00357
Secci D, Carradori S, Petzer A, Guglielmi P, D’Ascenzio M, Chimenti P, Bagetta D, Alcaro S, Zengin G. Petzer JP, Ortuso F. 2019. 4-(3-Nitrophenyl)thiazol-2-ylhydrazone derivatives as antioxidants and selective hMAO-B inhibitors: Synthesis, biological activity and computational analysis. Journal of Enzyme Inhibition and Medicinal Chemistry. 34(1): 597-612. https://doi.org/10.1080/14756366.2019.1571272
Takao K, Saito T, Chikuda D, Sugita Y. 2016. 2-Azolylchromone derivatives as potent and selective inhibitors of monoamine oxidases A and B. Chemical and Pharmaceutical Bulletin. 64(10): 1499-1504. https://doi.org/10.1248/cpb.c16-00527
Teo KC, Ho S. 2013. Monoamine oxidase-B ( MAO-B ) inhibitors : Implications for disease-modification in Parkinson ’ s disease. 2(19): 1–10. https://doi.org/10.1186/2047-9158-2-19
Youdim MBH, Bakhle YS. 2006. Monoamine oxidase: Isoforms and inhibitors in Parkinson’s disease and depressive illness. British Journal of Pharmacology. 147(Suppl 1): S287-S296.https://doi.org/10.1038/sj.bjp.0706464.
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