통합자연과학논문집 (Journal of Integrative Natural Science)

조선대학교 기초과학연구원 (The Basic Science Institute Chosun University)
권호 표지
DOI QR코드

DOI QR Code

Ligand-Based CoMFA Study on Pyridylpyrazolopyridine Derivatives as PKCθ Kinase Inhibitors

  • Balasubramanian, Pavithra K. (Department of Bio-New Drug Development, College of Medicine, Chosun University) ;
  • Balupuri, Anand (Department of Bio-New Drug Development, College of Medicine, Chosun University) ;
  • Cho, Seung Joo (Department of Bio-New Drug Development, College of Medicine, Chosun University)
  • 투고 : 2014.12.01
  • 심사 : 2014.12.25
  • 발행 : 2014.12.31
PDF 다운로드
⟨ 이전 논문 다음 논문 ⟩

초록

Protein kinase C theta (PKC-${\theta}$) is a serine/threonine specific protein kinase. It is largely expressed in the T-cells and CD28 signaling. PKC-${\theta}$ phosphorylates diverse proteins that are involved in the various cellular signaling pathways. Activated PKC-${\theta}$ in turn activates other transcription factors that control the proliferation and differentiation of T- cells. PKC-${\theta}$ is considered to be an interesting therapeutic target due to its crucial role in the proliferation, differentiation and survival of T-cells. In the present study, we have performed ligand-based CoMFA study on a series of pyridylpyrazolopyridine derivatives as PKC-${\theta}$ inhibitors. An acceptable CoMFA model ($q^2$=0.544; ONC=4; $r^2$=0.876) was developed and validated by Bootsrapping and progressive sampling. The CoMFA contour map suggested the regions to increase the activity. Bulky substitutions in R2 position of the piperizine ring could increase the activity. Similarly positive, small substitution in the R1 position of the Pyridine ring could considerably increase the activity. Our work could assist in designing more potent PKC-${\theta}$ inhibitors of pyridylpyrazolopyridine derivatives.

키워드

참고문헌

  1. T. Yamaguchi, M. Suzuki, H. Kimura, and M. Kato, "Role of Protein Kinase C in Eosinophil Function", Allergology International, Vol. 55, pp. 245-252, 2006. https://doi.org/10.2332/allergolint.55.245
  2. A.C. Newton, "Regulation of protein kinase C", Curr. Opin. Cell Biol., Vol. 9, pp. 161-167, 1997. https://doi.org/10.1016/S0955-0674(97)80058-0
  3. S. Manicassamy, S. Gupta, and Z. Sun, "Selective function of PKC-theta in T cells". Cell Mol. Immunol., Vol. 3, pp. 263-270, 2006.
  4. A. Altman, N. Isakov, and G. Baier, "Protein kinase C-${\theta}$: a new essential superstar on the T-cell stage", Immunology Today, Vol. 21, pp. 567-573, 2000. https://doi.org/10.1016/S0167-5699(00)01749-7
  5. B. Bauer, N. Krumbock, and N. Ghaffari-Tabrizi et al., "T cell expressed $PKC{\theta}$ demonstrates cell-type selective function", Eur. J. Immunol., Vol. 30 pp. 3645-3654, 2000. https://doi.org/10.1002/1521-4141(200012)30:12<3645::AID-IMMU3645>3.0.CO;2-#
  6. M. Kwon, R. Wang, J. Ma, and Z. Sun, "PKC-${\theta}$ is a drug target for prevention of T cell-mediated autoimmunity and allograft rejection", Endocrine, Metabolic & Immune Disorders Drug Targets, Vol. 10, pp. 367-372, 2010. https://doi.org/10.2174/1871530311006040367
  7. K. Hayashi and A. Altman, "Protein kinase C theta ($PKC{\theta}$): A key player in T cell life and death", Pharmacol. Res., Vol. 55, pp. 537-544, 2007. https://doi.org/10.1016/j.phrs.2007.04.009
  8. S. Chand, N. Mehta, M. S. Bahia, A. Dixit, and O. Silakari. "Protein kinase C-theta inhibitors: a novel therapy for inflammatory disorders", Curr. Pharm. Design, Vol. 18, pp. 4725-4746, 2012. https://doi.org/10.2174/138161212802651625
  9. C. F. Yang and M. G. Kazanietz, "Divergence and complexities in DAG signaling: looking beyond PKC", Trends Pharmacol. Sci., Vol. 24, pp. 602-608, 2003. https://doi.org/10.1016/j.tips.2003.09.003
  10. G. Baier and J. Wagner, "PKC inhibitors: potential in T cell-dependent immune diseases", Curr. Opin. Cell Biol., Vol. 21, pp. 262-267, 2009. https://doi.org/10.1016/j.ceb.2008.12.008
  11. P. K. Balasubramanian, A. Balupuri, and S. J. Cho, "A CoMFA study of phenoxypyridine-based JNK3 inhibitors using various partial charge schemes", J. Chosun Natural Sci., Vol. 7, pp. 45-49, 2014. https://doi.org/10.13160/ricns.2014.7.1.45
  12. P. K. Balasubramanian and S. J. Cho, "HQSAR analysis on novel series of 1-(4-phenylpiperazin-1-yl-2-(1H-Pyrazol-1-yl) ethanone derivatives targeting CCR1", J. Chosun Natural Sci., Vol. 6, pp. 163-169, 2013. https://doi.org/10.13160/ricns.2013.6.3.163
  13. A. Balupuri and S. J. Cho, "Exploration of the binding mode of indole derivatives as potent HIV-1 inhibitors using molecular docking simulations", J. Chosun Natural Sci., Vol. 6, pp. 138-142, 2013. https://doi.org/10.13160/ricns.2013.6.3.138
  14. C. G. Gadhe and S. J. Cho, "Importance of silicon atom in the drug design process", J. Chosun Natural Sci., Vol. 5, pp. 229-232, 2012. https://doi.org/10.13160/ricns.2012.5.4.229
  15. S. J. Cho, "The importance of halogen bonding: a tutorial", J. Chosun Natural Sci., Vol. 5, pp. 195-197, 2012. https://doi.org/10.13160/ricns.2012.5.3.195
  16. J. M. Jimenez, D. Boyall, and G. Brenchley, P. N. Collier, C. J. Davis, D. Fraysse, S. B. Keily, J. Henderson, A. Miller, F. Pierard, L. Settimo, H. C. Twin, C. M. Bolton, A. P. Curnock, P. Chiu, A. J. Tanner, and S. Young, "Design and optimization of selective protein kinase C ${\theta}$ ($PKC{\theta}$) inhibitors for the treatment of autoimmune diseases". J. Med. Chem., Vol. 56, pp. 1799-1810, 2013. https://doi.org/10.1021/jm301465a
  17. SYBYLx2.1, Tripos International, 1699 South Hanley Road, St. Louis, Missouri, 63144, USA.
  18. R. D. Cramer, D. E. Patterson, and J. D. Bunce, "Comparative molecular field analysis (CoMFA). 1. Effect of shape on binding of steroids to carrier proteins", J. Am. Chem. Soc., Vol. 110, pp. 5959-5967, 1988. https://doi.org/10.1021/ja00226a005

피인용 문헌

  1. 3D QSAR Study on Pyrrolopyrimidines-Based Derivatives as LIM2 Kinase Inhibitors vol.8, pp.4, 2015, https://doi.org/10.13160/ricns.2015.8.4.285
  2. A CoMFA Study of Quinazoline-based Anticancer Agents vol.8, pp.3, 2015, https://doi.org/10.13160/ricns.2015.8.3.214
  3. Comparative Molecular Field Analysis of Pyrrolopyrimidines as LRRK2 Kinase Inhibitors vol.9, pp.1, 2016, https://doi.org/10.13160/ricns.2016.9.1.1
  4. A CoMFA Study of Glycogen Synthase Kinase 3 Inhibitors vol.8, pp.1, 2015, https://doi.org/10.13160/ricns.2015.8.1.40