Journal of Integrative Natural Science (통합자연과학논문집)

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

DOI QR Code

Molecular Docking Studies of p21-Activated Kinase-1 (PAK1) Inhibitors

  • Balupuri, Anand (Department of Biomedical Sciences, College of Medicine, Chosun University) ;
  • Balasubramanian, Pavithra K. (Department of Biomedical Sciences, College of Medicine, Chosun University) ;
  • Cho, Seung Joo (Department of Cellular and Molecular Medicine, College of Medicine, Chosun University)
  • Received : 2016.07.18
  • Accepted : 2016.09.25
  • Published : 2016.09.30
Download PDF
⟨ Previous Next ⟩

Abstract

The p21-activated kinase-1 (PAK1) has emerged as a potential target for anticancer therapy. It is overexpressed in ovarian, breast and bladder cancers. This suggests that PAK1 may contribute to tumorigenesis. 4-azaindole derivatives are reported as potent PAK1 inhibitors. The present work deals with the molecular docking studies of 4-azaindoles with PAK1. Probable binding mode of these inhibitors has been identified by molecular modeling. Docking results indicated that hydrogen bonding interactions with Glu345 and Leu347 are responsible for governing inhibitor potency of the compounds. Additionally, Val284, Val328, Met344 and Leu396 were found to be accountable for hydrophobic interactions inside the active site of PAK1.

Keywords

References

  1. M. Lei, W. Lu, W. Meng, M.-C. Parrini, M. J. Eck, B. J. Mayer, and S. C. Harrison, "Structure of PAK1 in an Autoinhibited Conformation Reveals a Multistage Activation Switch", Cell, Vol. 102, pp. 387-397, 2000. https://doi.org/10.1016/S0092-8674(00)00043-X
  2. R. Kumar, A. E. Gururaj, and C. J. Barnes, "p21-activated kinases in cancer", Nat. Rev. Cancer, Vol. 6, pp. 459-471, 2006. https://doi.org/10.1038/nrc1892
  3. Z. M. Jaffer and J. Chernoff, "p21-activated kinases: three more join the Pak", Int. J. Biochem. Cell Biol., Vol. 34, pp. 713-717, 2002. https://doi.org/10.1016/S1357-2725(01)00158-3
  4. B. Dummler, K. Ohshiro, R. Kumar, and J. Field, "Pak protein kinases and their role in cancer", Cancer Metast. Rev., Vol. 28, pp. 51-63, 2009. https://doi.org/10.1007/s10555-008-9168-1
  5. C. C. Ong, A. M. Jubb, P. M. Haverty, W. Zhou, V. Tran, T. Truong, H. Turley, T. O'Brien, D. Vucic, A. L. Harris, M. Belvin, L. S. Friedman, E. M. Blackwood, H. Koeppen, and K. P. Hoeflich, "Targeting p21-activated kinase 1 (PAK1) to induce apoptosis of tumor cells", P. Natl. Acad. Sci. U.S.A., Vol. 108, pp. 7177-7182, 2011. https://doi.org/10.1073/pnas.1103350108
  6. 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
  7. A. Balupuri, P. K. Balasubramanian, and S. J. Cho, "A CoMFA study of glycogen synthase kinase 3 inhibitors", J. Chosun Natural Sci., Vol. 8, pp. 40-47, 2015. https://doi.org/10.13160/ricns.2015.8.1.40
  8. A. Balupuri, P. K. Balasubramanian, and S. J. Cho, "A CoMFA study of quinazoline-based anticancer agents", J. Chosun Natural Sci., Vol. 8, pp. 214-220, 2015. https://doi.org/10.13160/ricns.2015.8.3.214
  9. A. Balupuri, P. K. Balasubramanian, and S. J. Cho, "Comparative molecular field analysis of pyrrolopyrimidines as LRRK2 kinase inhibitors", J. Chosun Natural Sci., Vol. 9, pp. 1-9, 2016. https://doi.org/10.13160/ricns.2016.9.1.1
  10. 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
  11. W. Lee, J. J. Crawford, I. Aliagas, L. J. Murray, S. Tay, W. Wang, C. E. Heise, K. P. Hoeflich, H. La, S. Mathieu, R. Mintzer, S. Ramaswamy, L. Rouge, and J. Rudolph, "Synthesis and evaluation of a series of 4-azaindole-containing p21-activated kinase-1 inhibitors", Bioorg. Med. Chem. Lett., Vol. 26, pp. 3518-3524, 2016. https://doi.org/10.1016/j.bmcl.2016.06.031
  12. SYBYLx2.1, Tripos International, 1699 South Hanley Road, St. Louis, Missouri, 63144, USA.
  13. M. F. Sanner, "Python: a programming language for software integration and development", J. Mol. Graph. Model., Vol. 17, pp. 57-61, 1999.
  14. S. T. Staben, J. A. Feng, K. Lyle, M. Belvin, J. Boggs, J. D. Burch, C. C. Chua, H. Cui, A. G. Dipasquale, L. S. Friedman, C. Heise, H. Koeppen, A. Kotey, R. Mintzer, A. Oh, D. A. Roberts, L. Rouge, J. Rudolph, C. Tam, W. Wang, Y. Xiao, A. Young, Y. Zhang, and K. P. Hoeflich, "Back pocket flexibility provides group II p21-activated kinase (PAK) selectivity for type I 1/2 kinase inhibitors", J. Med. Chem., Vol. 57, pp. 1033-1045, 2014. https://doi.org/10.1021/jm401768t
  15. G. M. Morris, R. Huey, W. Lindstrom, M. F. Sanner, R. K. Belew, D. S. Goodsell, and A. J. Olson, "AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility", J. Comput. Chem., Vol. 30, pp. 2785-2791, 2009. https://doi.org/10.1002/jcc.21256
  16. G. M. Morris, D. S. Goodsell, R. S. Halliday, R. Huey, W. E. Hart, R. K. Belew, and A. J. Olson, "Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function", J. Comput. Chem., Vol. 19, pp. 1639-1662, 1998. https://doi.org/10.1002/(SICI)1096-987X(19981115)19:14<1639::AID-JCC10>3.0.CO;2-B

Cited by

  1. Cytotoxic Desulfated Saponin from Holothuria atra Predicted to Have High Binding Affinity to the Oncogenic Kinase PAK1: A Combined In Vitro and In Silico Study vol.86, pp.3, 2018, https://doi.org/10.3390/scipharm86030032