DOI QR코드

DOI QR Code

3D-QSAR Studies on 2-(indol-5-yl)thiazole Derivatives as Xanthine Oxidase (XO) Inhibitors

Nagarajan, Santhosh Kumar;Madhavan, Thirumurthy

  • 투고 : 2015.11.28
  • 심사 : 2015.12.25
  • 발행 : 2015.12.30

초록

Xanthine Oxidase is an enzyme, which oxidizes hypoxanthine to xanthine, and xanthine to uric acid. It is widely distributed throughout various organs including the liver, gut, lung, kidney, heart, brain and plasma. It is involved in gout pathogenesis. In this study, we have performed Comparative Molecular Field Analysis (CoMFA) on a series of 2-(indol-5-yl) thiazole derivatives as xanthine oxidase (XO) inhibitors to identify the structural variations with their inhibitory activities. Ligand based CoMFA models were generated based on atom-by-atom matching alignment. In atom-by-atom matching, the bioactive conformation of highly active molecule 11 was generated using systematic search. Compounds were aligned using the bioactive conformation and it is used for model generation. Different CoMFA models were generated using different alignments and the best model yielded a cross-validated $q^2$ of 0.698 with five components and non-cross-validated correlation coefficient ($r^2$) of 0.992 with Fisher value as 236.431, and an estimated standard error of 0.068. The predictive ability of the best CoMFA models was found to be $r^2_{pred}$0.653. The CoMFA study revealed that the $R_3$ position of the structure is important in influencing the biological activity of the inhibitors. Electro positive groups and bulkier substituents in this position enhance the biological activity.

키워드

Xanthine Oxidase;Gout;3D-QSAR;CoMFA

참고문헌

  1. P. Pacher, A Nivorozhkin, and C. Szabo, "Therapeutic effects of xanthine oxidase inhibitors: Renaissance half a century after the discovery of allopurinol", Pharmacol. Rev., Vol. 58, pp. 87-114, 2006. https://doi.org/10.1124/pr.58.1.6
  2. D. A. Parks and D. N. Granger, "Xanthine oxidase: Biochemistry, distribution and hysiology", Acta Physiologica Scandinavica. Supplementum, Vol. 548, pp. 87-99, 1986.
  3. M. Cicoira, L. Zanolla, A. Rossi, G. Golia, L. Franceschini, G. Brighetti, P. Zeni, and P. Zardini, "Elevated serum uric acid levels are associated with diastolic dysfunction in patients with dilated cardiomyopathy", Am. Heart J., Vol. 143, pp. 1107- 1111, 2002. https://doi.org/10.1067/mhj.2002.122122
  4. K. D. Pfeffer, T. P. Huecksteadt, and J. R. Hoidal, "Xanthine dehydrogenase and xanthine oxidase activity and gene expression in renal epithelial cells. cytokine and steroid regulation", J. Immunol., Vol. 153, pp. 1789-1797, 1994.
  5. R. Guerciolini, C. Szumlanski, and R. M. Weinshilboum, "Human liver xanthine oxidase: nature and extent of individual variation", Clin. Pharmacol. Ther., Vol. 50, pp. 663-672, 1991. https://doi.org/10.1038/clpt.1991.205
  6. R. Harrison, "Structure and function of xanthine oxidoreductase: Where are we now?", Free Radical Bio. Med., Vol. 33, pp. 774-797, 2002. https://doi.org/10.1016/S0891-5849(02)00956-5
  7. R. Harrison, "Physiological roles of xanthine oxidoreductase". Drug Metab. Rev., Vol. 36, pp. 363-375, 2004. https://doi.org/10.1081/DMR-120037569
  8. H. M. Kramer and G. Curhan, "The association between gout and nephrolithiasis: the national Hhealth and nutritieExamination survey III, 1988- 1994", Am. J. Kidney Dis., Vol. 40, pp. 37-42, 2002. https://doi.org/10.1053/ajkd.2002.33911
  9. H. K. Choi and G. Curhan, "Gout: Epidemiology and lifestyle choices", Curr. Opin. Rheumatol., Vol. 17, pp. 341-345, 2005.
  10. R. L. Wortmann, "Recent advances in the management of gout and hyperuricemia", Curr. Opin. Rheumatol., Vol. 17, pp. 319-324, 2005. https://doi.org/10.1097/01.bor.0000162060.25895.a5
  11. J. George and A. D. Struthers, "The role of urate and xanthine oxidase Inhibitors in cardiovascular disease", Cardiovascular Drug Reviews, Vol. 58, pp. 59-64, 2008.
  12. N. Dalbeth and L. Stamp, "Allopurinol dosing in renal impairment: Walking the tightrope between adequate urate lowering and adverse events", Seminars in Dialysis, Vol. 20, pp. 391-395, 2007. https://doi.org/10.1111/j.1525-139X.2007.00270.x
  13. T.-F. Tsai and T.-Y. Yeh, "Allopurinol in dermatology", Am. J. Clin. Dermatol., Vol. 11, pp. 225-232, 2010. https://doi.org/10.2165/11533190-000000000-00000
  14. B. L. Love, R. Barrons, A. Veverka, and K. M. Snider, "Urate-lowering therapy for gout: focus on febuxostat", Pharmacotherapy, Vol. 30, pp. 594-608, 2010. https://doi.org/10.1592/phco.30.6.594
  15. J. U. Song, S. P. Choi, T. H. Kim, C.-K. Jung, J.- Y. Lee, S.-H. Jung, and G. T. Kim, "Design and synthesis of novel 2-(indol-5-yl)thiazole derivatives as xanthine oxidase inhibitors", Bioorg. Med. Chem. Lett., Vol. 25, pp. 1254-1258, 2015. https://doi.org/10.1016/j.bmcl.2015.01.055
  16. K. Abe, H. Shimokawa, K. Morikawa, T. Uwatoku, K. Oi, Y. Matsumoto, T. Hattori, Y. Nakashima, K. Kaibuchi, K. Sueishi, and A. Takeshit, "Long-term treatment with a Rho-kinase inhibitor improves monocrotaline-induced fatal pulmonary hypertension in rats", Circ. Res., Vol. 94, pp. 385-393, 2004. https://doi.org/10.1161/01.RES.0000111804.34509.94
  17. T. Ishizaki, M. Uehata, I. Tamechika, J. Keel, K. Nonomura, M. Maekawa, and S. Narumiya, "Pharmacological properties of Y-27632, a specific inhibitor of Rho-associated kinases", Mol. Pharmacol., Vol. 57, pp. 976-983, 2000.
  18. P. Geladi and B. R. Kowalski, "Partial least-squares regression: a tutorial", Anal. Chim. Acta, Vol. 185, pp. 1-17, 1986. https://doi.org/10.1016/0003-2670(86)80028-9
  19. S. Wold, "Cross-validatory estimation of the number of components in factor and principal components models", Technometrics, Vol. 20, pp. 397-406, 1978. https://doi.org/10.1080/00401706.1978.10489693
  20. B. Sathya and T. Madhavan, "Comparative molecular field analysis of caspase-3 Inihibitors", J. Choun Natural Sci., Vol. 7, pp. 166-172, 2014. https://doi.org/10.13160/ricns.2014.7.3.166
  21. P. Singh and T. Madhavan, "Histone deactylase inhibitors as novel target for cancer, diabetes, and inflammation", J. Chosun Natural Sci., Vol. 6, pp. 57-63, 2013. https://doi.org/10.13160/ricns.2013.6.1.057
  22. S. Kulkarni and T. Madhavan, "Application of docking methods: an effective in Silico tool for drug design", J. Chosun Natural Sci., Vol. 6, pp. 100-103, 2013. https://doi.org/10.13160/ricns.2013.6.2.100
  23. M. Shalini and T. Madhavan, "Homology modeling of CCR 4: novel therapeutic target and preferential maker for Th2 Cells", J. Chosun Natural Sci., Vol. 7, pp. 234-240, 2014. https://doi.org/10.13160/ricns.2014.7.4.234
  24. B. Sathya and T. Madhavan, "Comparative molecular mimilarity indices analysis of caspase-3 inhibitors", J. Chosun Natural Sci., Vol. 7, pp. 227- 233, 2014. https://doi.org/10.13160/ricns.2014.7.4.227

피인용 문헌

  1. Comparative Molecular Similarity Index Analysis on 2-(indol-5-yl)thiazolederivatives as Xanthine Oxidase(XO)inhibitors vol.9, pp.3, 2016, https://doi.org/10.13160/ricns.2015.8.4.258