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Hologram Quantitative Structure Activity Relationship Analysis of JNK Antagonists

  • Kulkarni, Seema A. (Department of Biotechnology, Karpaga Vinayaga college of Engineering and Technology) ;
  • Madhavan, Thirumurthy (Department of Bioinformatics, School of Bioengineering, SRM University)
  • Received : 2015.04.22
  • Accepted : 2015.06.25
  • Published : 2015.06.30

Abstract

c-Jun N-terminal kinase-3 (JNK3) is a member of the mitogen-activated protein kinase family (MAPK), and plays an important role in neurological disorders. Therefore, identification of selective JNK3 inhibitor may contribute towards neuroprotection therapies. In this work, we performed hologram quantitative structure-activity relationship (HQSAR) on a series of thiophene trisubstituted derivatives. The best predictions were obtained for HQSAR model with $q^2=0.628$ and $r^2=0.986$. Statistical parameters from the generated QSAR models indicated the data is well fitted and have high predictive ability. HQSAR result showed that atom, bond and chirality descriptors play an important role in JNK3 activity and also shows that electronegative groups is highly favourble to enhance the biological activity. Our results could be useful to design novel and selective JNK3 inhibitors.

Keywords

References

  1. S. Bowers, A. P. Truong, R. J. Neitz, R. K. Hom, J. M. Sealy, G. D. Probst, D. Quincy, B. Peterson, W. Chan, R. A. Galemmo Jr., A. W. Konradi, H. L. Sham, G. Toth, H. Pan, M. Lin, N. Yao, D. R. Artis, H. Zhang, L. Chen, M. Dryer, B. Samant, W. Zmolek, K. Wong, C. Lorentzen, E. Goldbach, G. Tonn, K.P. Quinn, J.-M. Sauer, S. Wright, K. Powell, L. Ruslim, Z. Ren, F. Bard, and T.A. Yednock, "Design and synthesis of brain penetrant selective JNK inhibitors with improved pharmacokinetic properties for the prevention of neurodegeneration", Bioorg. Med. Chem. Lett., Vol. 21, pp. 5521-5527, 2011. https://doi.org/10.1016/j.bmcl.2011.06.100
  2. F. Hilberg, A. Aguzzi, N. Howells, and E.F Wagner, "c-Jun is essential for normal mouse development and hepatogenesis", Nature, Vol. 365, pp. 179-181, 1993. https://doi.org/10.1038/365179a0
  3. G. Klebe, "The use of composite crystal-field environments in molecular recognition and the de novo design of protein ligands", J. Mol. Biol., Vol. 237, pp. 212-235, 1994. https://doi.org/10.1006/jmbi.1994.1223
  4. R. Wisdom, R.S Johnson, and C Moore, "c-Jun regulates cell cycle progression and apoptosis by distinct mechanisms", EMBO J., Vol. 18, pp. 188-197, 1999. https://doi.org/10.1093/emboj/18.1.188
  5. A. Behrens, W. Jochum, M. Sibilia, and E. F Wagner, "Oncogenic transformation by ras and fos is mediated by c-Jun N-terminal phosphorylation", Oncogene, Vol. 19, pp. 2657-2663, 2000. https://doi.org/10.1038/sj.onc.1203603
  6. L. A. Tibbles, Y. L. Ing, F. Kiefer, N. Iscove, J. R. Woodgett, and N. J. Lassam , "MLK-3 activates the SAPK/JNK and p38/RK pathways via SEK1 and MKK3/6", EMBO J., Vol. 15, pp. 7026-7035, 1996.
  7. D. D. Yang, D. Conze, A. J. Whitmarsh, T. Barrett, R. J. Davis, M. Rincón, and R. A. Flavell, "Differentiation of CD4+ cells to Th1 cells requires MAP kinase JNK2", Immunity, Vol. 9, pp. 575-585, 1998. https://doi.org/10.1016/S1074-7613(00)80640-8
  8. C. G. Gadhe, T. Madhavan, G. Kothandan, and S. J. Cho, "In Silico quantitative structure-activity relationship studies on P-gp modulators of tetrahydroisoquinoline- ethyl-phenylamine series", BMC Struct. Biol., Vol. 11, 2011.
  9. T. Madhavan, J. Y. Chung, G. Kothandan, C. G. Gadhe, and S. J. Cho, "3D-QSAR studies of JNK1 inhibitors utilizing various alignment methods", Chem. Biol. Drug. Des., Vol. 79, pp.53-67, 2012. https://doi.org/10.1111/j.1747-0285.2011.01168.x
  10. R. D. Cramer, D. E. Patterson, and J. 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