Skip to main content

Advertisement

Springer Nature Link
Log in

A comparative study of AutoDock and PMF scoring performances, and SAR of 2-substituted pyrazolotriazolopyrimidines and 4-substituted pyrazolopyrimidines as potent xanthine oxidase inhibitors

  • Published:
Journal of Computer-Aided Molecular Design Aims and scope Submit manuscript

Abstract

4-Alkylidenehydrazino-1H-pyrazolo[3,4-d]pyrimidines, 4-arylmethylidenehydrazino-1H-pyrazolo[3,4-d]pyrimidines, and 2-substituted 7H-pyrazolo[4,3-e]-1,2,4-triazolo-[1,5-c]-pyrimidines as potential xanthine oxidase inhibitors were docked into the active site of the bovine milk xanthine dehydrogenase using two scoring functions involved in AutoDock 3.05 and the CAChe 6.1.10. The correlation coefficiency obtained between the AutoDock binding energy and IC50 of the inhibitors was better than that obtained by the CAChe-PMF docking score. Many ligands exhibited one to four hydrogen bonds within the active site, where the detected hydrogen bonds by CAChe was identified quantitatively in the docked conformation by using MOPAC 2002. These ligands were docked into a long, narrow channel of the enzyme leading to the molybdopterin active moiety, with hydrogen bonding and electrostatic interaction between the planar aromatic moiety of the ligand and the enzyme. Furthermore, SAR among inhibitors was investigated, which revealed that the oxo group of pyrazolopyrimidine analogs is essential for its activity and the tricyclic derivatives are shown to be more potent than bicyclic ones. The mode of interaction of the docked inhibitors was described in details.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Scheme 1
Fig. 1
Fig. 2
Scheme 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10

Similar content being viewed by others

References

  1. Nagamatsu T, Fujita T, Endo K (2000) Perkin 1:33

    Article  Google Scholar 

  2. Nagamatsu T, Ukai M, Yoneda F, Brown DJ (1985) Chem Pharm Bull 33:3113

    CAS  Google Scholar 

  3. Nagamatsu T, Yamasaki H (1995) J Chem Soc Chem Commun 19:2041

    Article  Google Scholar 

  4. Nagamatsu T, Yamasaki H, Akiyama T, Hara S, Mori K, Kusakabe H (1999) Synthesis 4:655

    Article  Google Scholar 

  5. Nagamatsu T, Fujita T (1999) Chem Commun (Cambridge) 16:1461

    Article  Google Scholar 

  6. Sato S, Tatsumi K, Takahashi T (1991) Purine and pyrimidine matabolism in man. Plenum, New York

    Google Scholar 

  7. Elion GB, Callahan S, Nathan H, Bieber S, Rundles RW, Hitchings GH (1963) Biochem Pharmacol 12:85

    Article  CAS  Google Scholar 

  8. Chien S-C, Yang C-W, Tseng Y-H, Tsay H-S, Kuo Y-H, Wang S-Y (2009) Planta Med 75:302

    Article  CAS  Google Scholar 

  9. Chohan S, Becker MA (2009) Curr Opin Rheumatol 21:143

    Article  CAS  Google Scholar 

  10. Edwards NL (2009) Rheumatology, vol 48, p 1115. Oxford

  11. Haba M, Kinoshita H, Matsuda N, Azma T, Hama-Tomioka K, Hatakeyama N, Yamazaki M, Hatano Y (2009) Anesthesiology 111:279

    Article  CAS  Google Scholar 

  12. Maitraie D, Hung C-F, Tu H-Y, Liou Y-T, Wei B-L, Yang S-C, Wang J-P, Lin C-N (2009) Bioorg Med Chem 17:2785

    Article  CAS  Google Scholar 

  13. Mukhopadhyay P, Rajesh M, Batkai S, Kashiwaya Y, Hasko G, Liaudet L, Szabo C, Pacher P (2009) Am J Physiol 296:H1466

    CAS  Google Scholar 

  14. Murata K, Nakao K, Hirata N, Namba K, Nomi T, Kitamura Y, Moriyama K, Shintani T, Iinuma M, Matsuda H (2009) J Nat Med 63:355

    Article  CAS  Google Scholar 

  15. Sousa C, Pereira DM, Valentao P, Ferreres F, Pereira JA, Seabra RM, Andrade PB (2009) J Agric Food Chem 57:2288

    Article  CAS  Google Scholar 

  16. Tan W-J, Xu J-C, Li L, Chen K-L (2009) Nat Prod Res Part B 23:393

    Article  CAS  Google Scholar 

  17. Xiao J, She Q (2008) Xinxueguan Bingxue Jinzhan 29:622

    CAS  Google Scholar 

  18. George J, Struthers AD (2008) Cardiovasc Ther 26:59

    CAS  Google Scholar 

  19. George J, Struthers AD (2009) Vasc Health Risk Manage 5:265

    CAS  Google Scholar 

  20. Fang J, Seki T, Maeda H (2009) Adv Drug Delivery Rev 61:290

    Article  CAS  Google Scholar 

  21. Lin H-C, Tsai S-H, Chen C-S, Chang Y-C, Lee C-M, Lai Z-Y, Lin C-M (2008) Biochem Pharmacol 75:1416

    Article  CAS  Google Scholar 

  22. Prusis P, Dambrova M, Andrianov V, Rozhkov E, Semenikhina V, Piskunova I, Ongwae E, Lundstedt T, Kalvinsh I, Wikberg JES (2004) J Med Chem 47:3105

    Article  CAS  Google Scholar 

  23. Lin C-M, Chen C-S, Chen C-T, Liang Y-C, Lin J-K (2002) Biochem Biophys Res Commun 294:167

    Article  CAS  Google Scholar 

  24. Wang R, Lu Y, Wang S (2003) J Med Chem 46:2287

    Article  CAS  Google Scholar 

  25. CAChe (2000–2004) Work system pro version 6.1.10. Fujitsu Limited, Japan

  26. Muegge I, Martin YC (1999) J Med Chem 42:791

    Article  CAS  Google Scholar 

  27. Muegge I (2000) Perspect Drug Discovery Des 20:99

    Article  CAS  Google Scholar 

  28. Muegge I (2001) J Comput Chem 22:418

    Article  CAS  Google Scholar 

  29. Okamoto K, Eger BT, Nishino T, Kondo S, Pai EF, Nishino T (2003) J Biol Chem 278:1848

    Article  CAS  Google Scholar 

  30. Okamoto K, Matsumoto K, Hille R, Eger BT, Pai EF, Nishino T (2004) Proc Natl Acad Sci USA 101:7931

    Article  CAS  Google Scholar 

  31. Ferrari AM, Degliesposti G, Sgobba M, Rastelli G (2007) Bioorg Med Chem 15:7865

    Article  CAS  Google Scholar 

  32. Warren GL, Andrews CW, Capelli A-M, Clarke B, LaLonde J, Lambert MH, Lindvall M, Nevins N, Semus SF, Senger S, Tedesco G, Wall ID, Woolven JM, Peishoff CE, Head MS (2006) J Med Chem 49:5912

    Article  CAS  Google Scholar 

  33. de Graaf C, Oostenbrink C, Keizers PHJ, van der Wijst T, Jongejan A, Vermeulen NPE (2006) J Med Chem 49:2417

    Article  Google Scholar 

  34. Morris GM, Goodsell DS, Halliday RS, Huey R, Hart WE, Belew RK, Olson AJ (1998) J Comput Chem 19:1639

    Article  CAS  Google Scholar 

  35. Meng EC, Kuntz ID, Abraham DJ, Kellogg GE (1994) J Comput Aided Mol Des 8:299

    Article  CAS  Google Scholar 

  36. Osada Y, Tsuchimoto M, Fukushima H, Takahashi K, Kondo S, Hasegawa M, Komoriya K (1993) Eur J Pharmacol 241:183

    Article  CAS  Google Scholar 

  37. Massey V, Edmondson D (1970) J Biol Chem 245:6595

    CAS  Google Scholar 

  38. Enroth C, Eger BT, Okamoto K, Nishino T, Nishino T, Pai EF (2000) Proc Natl Acad Sci USA 97:10723

    Article  CAS  Google Scholar 

  39. Stewart JJP (1990) J Comput Aided Mol Des 4:1

    Article  Google Scholar 

  40. Bolstad ES, Anderson AC (2009) Proteins 75:62

    Article  CAS  Google Scholar 

  41. Liang S, Meroueh SO, Wang G, Qiu C, Zhou Y (2009) Proteins 75:397

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported in part by Academic Frontier Grants-in-aid of the Ministry of Education, Science and Technology in Japan and we are grateful to the people in charge for the grant assignment.

Author information

Authors and Affiliations

  1. Division of Pharmaceutical Sciences, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 1-1-1 Tsushima-Naka, Okayama, 700-8530, Japan

    Hamed I. Ali, Takayuki Fujita & Tomohisa Nagamatsu

  2. Faculty of Pharmaceutical Sciences, Center for Area Research and Development (CARD), Kobe Gakuin University, 1-1-3 Minatojima, Chuo-ku, Kobe, 650-8586, Japan

    Eiichi Akaho

Authors
  1. Hamed I. Ali
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Takayuki Fujita
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Eiichi Akaho
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tomohisa Nagamatsu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Eiichi Akaho.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ali, H.I., Fujita, T., Akaho, E. et al. A comparative study of AutoDock and PMF scoring performances, and SAR of 2-substituted pyrazolotriazolopyrimidines and 4-substituted pyrazolopyrimidines as potent xanthine oxidase inhibitors. J Comput Aided Mol Des 24, 57–75 (2010). https://doi.org/10.1007/s10822-009-9314-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10822-009-9314-z

Keywords

Search

Navigation