QSAR Modeling of Compounds Derived from 1,2,3-Triazolopiperidine as DPP-4 Enzyme Inhibitors Using Semiempirical AM1

Anjar Purba Asmara, Reni Silvia Nasution, Rosi Minarty

Abstract

This study aims to model the derived compounds of 1,2,3-triazolopiperidine using sem­iempirical method AM1 and determine the further derivation with the better IC50 values against DPP-4 enzyme theoretically. This research employed ChemDraw Pro 12 software for for 2D struc­tural drawing, Hyperchem 8.0 for 3D modelling, and MLR statistical analysis for modeling QSAR equations. The semiempirical method was likely to be the appropriate platform to apply because the correlation coefficient of HNMR chemical shift between theoretical and actual value is rela­tively close, 0.8891. The multilinear regression analysis produced 4 equation models where the best one is equation 4 as detailed below:” IC50   = 875,5116 + (-7400,27*qH35) + (-0,00133* Eat.is) + (-3230,72* qN23) + (3,30277* µ)” n = 25; r2 = 0,594; Adjusted r2= 0,486; PRESS = 1,2× 104. Finally, the theoretically promising substituent was -CN possessing IC50 value = 1.61 nM. 

Keywords

triazolopiperidine derivatives; diabetes mellitus; DPP-4 inhibitor; QSAR

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References

H. D. Pranowo, Pengantar Kimia Komputasi, Bandung: Lubuk Agung, 2011.

">Google scholar

S. B. Utomo, F. Sanubari, B. Utami, & N.D. Nurhayati, “ Analysis of a quantita¬tive relationship between the structure and analgesic activity of meperidin derivatives using semi-empirical AM1 method”, JKPK (Jurnal Kimia dan Pendidikan kimia), vol. 2, no. 3, pp. 158-168, 2017.

DOI: 10.20961/jkpk.v2i3.12092

M. D Breyer,” Improving productivity of modern-day drug discovery”, Expert Opinion on Drug Discovery, vol. 9, no.2, pp.115-118, 2014

.DOI: 10.1517/17460441.2014.870150

W. Hui, M. Jiang, F. Sun, S. Li, C. Y. Hse, & C. Jin, , Screening, synthesis, and QSAR research on cinnamaldehyde-amino acid schiff base compounds as antibacterial agents. Molecules, Vol. 23, no.11, 2018.

.DOI: molecules23113027

A .P. Asmara, Mudasir, & D. Siswanta,” Penentuan metode komputasi untuk analisis hubungan kuantitatif struktur dan aktivitas senyawa turunan triazolopiperazin amida”. Elkawnie: Journal of Islamic Science and Technology, vol. 1, no.1, pp19-30, 2015.

DOI: 10.22373/ekw.v1i1.515

H. D. Pranowo, Kimia Komputasi. Yogyakarta: Pusat Kimia Komputasi UGM, 2000.

Google scholar

P. N. Malani. “Harrison’s Principles of Internal Medicine”, JAMA. vol. 308, no. 17, pp. 1813–1814,2012. doi:

DOI: 10.1001/jama.308.17.1813-b

Stehouwer CDA, Schaper NC. Therapeutic strategies in Diabetes. Oxford: Clinic.al Publishing, 2009

Google scholar

H. Yehuda, & Z. Bloomgarden, “ Diabetes In Youth: A Dilemma Of Pathogenesis”. Juornal Of Diabetes. Metabolic Institute Of America, vol. 3, no. 2, pp. 91-92, 2011.

DOI: 10.1111/j.1753-0407.2011.00127.x.

R. Gojka. "WHO Global report on diabetes: A summary." International Journal of Noncommunicable Diseases, vol. 1, no. 1, pp. 3-8, 2016.

Google scholar

J. J. Neumiller, L. Wood, & R. K. Campbell, “Dipeptidyl peptidase 4 (DPP-4) inhibitors for the treatment of type 2 diabetes mellitus”, Pharmacotherapy, vol. 30, no.5, pp463-484,2010.

DOI: 10.1592/phco.30.5.463.

Z. Shan, M. Peng, H. Fan, Q. Lu, P. Lu, C.Zhao, & Y. Chen, "Discovery of potent dipeptidyl peptidase IV inhibitors derived for the treatment of type 2 diabetes," Bioorganic & Medicinal Chemistry Letters, vol. 21, no. 6, pp. 1731–1735, 2011.

DOI: 10.1016/j.bmcl.2011.01.086 .

S. A. El-Karim, Y. M. Syama, M. A. Nael, H. F. Ali, & M. A. Motaleb, “Rational design and synthesis of new tetralin-sulfonamide derivatives as po-tent antidiabetics and DPP-4 inhibitors: 2D&3D QSAR, in vivo radio¬labeling and bio distribution studies”, Bioorganic Chemistry, vol. 81, pp. 481-493, 2018.

DOI: 10.1016/j.bioorg.2018.09.021,2018.`

A. P. Asmara, Mudasir, & D. Siswanta, "Analisis HKSA senyawa antidiabetik turunan triazolopiperazin amida menggunakan metode semiempirik PM3." Al-Chemy: Journal of Chemistry, vol. 5, no. 4, pp. 106–113, 2017.

DOI: 10.18860/al.v5i4.4045.`

K. Wijaya, I. Tahir, B. Purwono, & W. Dinni,” QSAR study of flavone/flavonol analogues as the antiradical compounds based on Hansch analysis”, Indonesian Journal of Chemistry, vol. 3, no. 1, pp. 48-54, 2003.

DOI: 10.18860/al.v5i4.4045.

F .Jensen, Introduction to Computational Chemistry. West Sussex: John Wiley & Sons, 2007.

Google scholar

I. Tahir & P. Iswanto, Hubungan kuantitatif struktur dan aktivitas antikanker senyawa turunan estradiol hasil perhitungan metode semiempiris AM1. Yogyakarta: Prosiding Seminar Nasional Kimia XV, ISSN 1410-8313, 2004.

Google scholar

P. E. Istyastono, S. Martono, H. D.Pranowo, & I. Tahir, “ Quantitative structure-activity relationship analysis of curcumin and its derivatives as gst inhibitors based on computational chemistry calculation”. Indonesian Journal of Chemistry, 3 (3), 179-186, 2003.

DOI: 10.22146/ijc.21886 .

H. D. Siswandono, Kimia Medisinal, Surabaya: Universitas Airlangga Press, 2000.

Google scholar

G. L Patrick, An Introduction to Medicinal Chemistry, Oxford: Oxford University Press, 2013.

Google scholar

C. Li, M. Hanif, X. Li, S. Zhang, Z. Xie, , L. Liu, B. Yang, S. Su, & Y. Ma, “ Effect of cyano-substitution in distyrylbenzene derivatives on their fluorescence and electroluminescence properties”. Journal of Materials Chemistry C, vol. 4, no. 31, pp. 7478–7484, 2016.

DOI: 10.1039/C6TC01886F/ijc.21886 .

S. Arulmozhiraja, N. Matsuo, E. Ishitsubo, S. Okazaki, H. Shimano, & H.Tokiwa, “Comparative Binding Analysis of Dipeptidyl Peptidase IV (DPP-4) with Antidiabetic Drugs – An Ab Initio Fragment Molecular Orbital Study. PLoS ONE, vol. 11, no.11, 2016

DOI: 10.1371/journal.pone.0166275.

K. Aertgeerts, S. Ye, M. G. Tennant, M. L. Kraus, J. O. E. Rogers, B. C. Sang, R. J. Skene, D. R. Webb, & G. S. Prasad, “Crystal structure of human dipeptidyl peptidase IV in complex with a decapeptide reveals details on substrate specificity and tetrahedral intermediate formation”, Protein Science, vol. 13, no. 2, pp. 412–421, 2004.

DOI: 10.1110/ps.03460604.

S. Q. Pantaleão, E. A. Philot, D. Resende-Lara, P. Túlio, A.N. Lima, D. Perahia, M. A. Miteva, A .L. Scott, & K. M. Honorio,” Structural dynamics of DPP-4 and its influence on the projection of bioactive ligands”, Molecules, vol. 23, no.2, pp.490, 2018.

DOI: 10.3390/molecules23020490.

D. Bhattacherjee, C. Basu, Q. Bhardwaj, S. Mal, S. Sahu, R. Sur, & K. P. Bhabak, “Design, Synthesis and Anti‐Cancer Activities of Benzyl Analogues of Garlic‐Derived Diallyl Disulfide (DADS) and the Corresponding Diselenides”, Chemistry Select, vol. 2, no. 24, pp. 7399–7406, 2017.

DOI: 10.1002/slct.201700499 .

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