Studi Penambatan Maya dan Prediksi Toksisitas Turunan 5-Fluorouridin Monofosfat Pada Enzim Orotidin-5-monofosfat Dekarboksilase

Andzar Fikranus Shofa, Anggie Fuji Lestari, Hafidh Agrestian Soputri, Kharisma Safenti

Abstract


Cancer is one of the leading causes of death in the world. Various cancer treatments had undergone many developments, one of which is through the process of drug discovery of cancer drugs. 5-Fluorouridine Monophosphate is a potential active metabolite of 5-fluorouracil and the ligand for the enzyme Orotidine-5-monophosphate decarboxylase (OMPD), so it deserves further development through structural modification. This study aims to predict the cytotoxic activity and toxicity of the parent compound 5-Fluorouridine Monophosphate and twenty derivative compounds as candidates for anticancer drugs. The mechanism of action of 5-Fluorouridine Monophosphate derivatives as anticancer by inhibiting OMPD, a carboxylation enzyme that is important in nucleotide biosynthesis in the process of cellular replication. Biological activity was predicted through molecular modeling called in silico assay using the Molegro Virtual Docker (MVD) program, while compound toxicity was predicted using the pkCSM online tools program. The in silico test is carried out by docking the compound whose activity will be predicted against the OMPD receptor target with the code PDB. 2QCF. The results of docking in the form of bond energy are indicated by the value of the Rerank Score (RS). Compounds that have a small RS value are predicted to have more stable ligand-receptor binding and have high activity. Based on the results of the in silico test, it can be concluded that all derivatives of 5-Fluorouridine Monophosphate meet the requirements of Lipinski's law. Then the results of molecular docking showed that the RS value of the derivative compound number 16 was lower than the parent compound 5-Fluorouridine Monophosphate, but had more hydrogen bonds with amino acid residues than the parent compound. Therefore, it can be concluded that the 16th derivative with the formula C16H25F2N2O7P is the most feasible to be synthesized and continued by testing its activity in vitro and in vivo.


Keywords


Anticancer; Molecular Docking; Orotidine-5-monophosphate decarboxylase; 5-Fluorouridine Monophosphate; 2QCF.

References


Chen, X. et al. (2020) “Analysis of the Physicochemical Properties of Acaricides Based on Lipinski’s Rule of Five,” Journal of Computational Biology, 27(9), pp. 1397–1406. doi:10.1089/cmb.2019.0323.

Ferreira, L.G. et al. (2015) “molecules Molecular Docking and Structure-Based Drug Design Strategies,” Molecules, 20, pp. 13384–13421. doi:10.3390/molecules200713384.

Filgueira de Azevedo Jr (2019) Docking Screens for Drug Discovery. Available at: http://www.springer.com/series/7651.

Gariano, R.F. et al. (1994) “Retinal toxicity of the antimetabolite 5-fluorouridine 5’-monophosphate administered intravitreally using multivesicular liposomes,” Retina (Philadelphia, Pa.), 14(1), p. 75—80. doi:10.1097/00006982-199401000-00015.

Kesuma, D. et al. (2018) “Uji in silico Aktivitas Sitotoksik dan Toksisitas Senyawa Turunan N-(Benzoil)-N’- feniltiourea Sebagai Calon Obat Antikanker,” JPSCR : Journal of Pharmaceutical Science and Clinical Research, 3(1), p. 1. doi:10.20961/jpscr.v3i1.16266.

Kusumaningrum, S. et al. (2014) “The molecular docking of 1,4-naphthoquinone derivatives as inhibitors of Polo-like kinase 1 using Molegro Virtual Docker,” Journal of Applied Pharmaceutical Science, 4(11), pp. 47–53. doi:10.7324/JAPS.2014.4119.

Sochacka, J. (2014) “Docking of thiopurine derivatives to human serum albumin and binding site analysis with Molegro Virtual Docker,” Acta Poloniae Pharmaceutica, 71(2), pp. 343–349. Available at: https://www.researchgate.net/publication/261175349 (Accessed: January 28, 2022).

Susanti, N.M.P. et al. (2018) “Molecular Docking Sianidin dan Peonidin Sebagai Antiinflamasi pada Aterosklerosis Secara In Silico,” Jurnal Farmasi Udayana, 7(1), pp. 28–33. Available at: https://www.rcsb.org/ (Accessed: January 25, 2022).

Torre, L.A. et al. (2016) “Global Cancer Incidence and Mortality Rates and Trends—An Update,” Cancer Epidemiology and Prevention Biomarkers, 25(1), pp. 16–27. doi:10.1158/1055-9965.EPI-15-0578.

Wittmann, J.G. et al. (2008) “Structures of the Human Orotidine-5′-Monophosphate Decarboxylase Support a Covalent Mechanism and Provide a Framework for Drug Design,” Structure, 16(1), pp. 82–92. doi:10.1016/j.str.2007.10.020.

Zein Muttaqin, F. et al. (2019) Studi Molecular Docking, Molecular Dynamic, dan Prediksi Toksisitas Senyawa Turunan Alkaloid Naftiridin Sebagai Inhibitor Protein Kinase 2-α pada Kanker Leukimia.


Full Text: PDF

DOI: 10.15408/pbsj.v3i2.24524

Refbacks

  • There are currently no refbacks.