Bulletin of the Korean Chemical Society

Korean Chemical Society (대한화학회)
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Inhibitor Design for Human Heat Shock Protein 70 ATPase Domain by Pharmacophore-based in silico Screening

  • Lee, Jee-Young (Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University) ;
  • Jung, Ki-Woong (Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University) ;
  • Kim, Yang-Mee (Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University)
  • Published : 2008.09.30
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Abstract

The 70 kDa heat-shock protein (Hsp70) involved in various cellular functions, such as protein folding, translocation and degradation, regulates apoptosis in cancer cells. Recently, it has been reported that the green tea flavonoid (−)-epigallocatechin 3-gallate (EGCG) induces apoptosis in numerous cancer cell lines and could inhibit the anti-apoptotic effect of human Hsp70 ATPase domain (hATPase). In the present study, docking model between EGCG and hATPase was determined using automated docking study. Epi-gallo moiety in EGCG participated in hydrogen bonds with side chain of K71 and T204, and has metal chelating interaction with hATPase. Hydroxyl group of catechin moiety also participated in metal chelating hydrogen bond. Gallate moiety had two hydrogen bondings with side chains of E268 and K271, and hydrophobic interaction with Y15. Based on this docking model, we determined two pharmacophore maps consisted of six or seven features, including three or four hydrogen bonding acceptors, two hydrogen bonding donors, and one lipophilic. We searched a flavonoid database including 23 naturally occurring flavonoids and 10 polyphenolic flavonoids with two maps, and myricetin and GC were hit by map I. Three hydroxyl groups of B-ring in myricetin and gallo moiety of GC formed important hydrogen bonds with hATPase. 7-OH of A-ring in myricetin and OH group of catechin moiety in GC are hydrogen bond donors similar to gallate moiety in EGCG. From these results, it can be proposed that myricetin and GC can be potent inhibitors of hATPase. This study will be helpful to understand the mechanism of inhibition of hATPase by EGCG and give insights to develop potent inhibitors of hATPase.

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References

  1. Chen, D.; Milacic, V.; Chen, M. S.; Wan, S. B.; Lam, W. H.; Huo, C.; Landis-Piwowar, K. R.; Cui, Q. C.; Wali, A.; Chan, T. H.; Dou, Q. P. Histol. Histopathol. 2008, 23, 487
  2. Katiyar, S. K.; Matsui, M. S.; Elmets, C. A.; Mukhtar, H. Photochem. Photobiol. 1999, 69, 148
  3. Xu, Z.; Chen, S.; Li, X.; Luo, G.; Li, L.; Le, W. Neurochem. Res. 2006, 31, 1263 https://doi.org/10.1007/s11064-006-9166-z
  4. Qanungo, S.; Das, M.; Haldar, S.; Basu, A. Carcinogenesis 2005, 26, 958 https://doi.org/10.1093/carcin/bgi040
  5. Brierley-Hobson, S. Bioscience Horizons 2008, 1, 9 https://doi.org/10.1093/biohorizons/hzn002
  6. Ermakova, S. P.; Kang, B. S.; Choi, B. Y.; Choi, H. S.; Schuster, T. F.; Ma, W. Y.; Bode, A. M.; Dong, Z. Cancer Res. 2006, 66, 9260
  7. Aghdassi, A.; Phillips, P.; Dudeja, V.; Dhaulakhandi, D.; Sharif, R.; Dawra, R.; Lerch, M. M.; Saluja, A. Cancer Res. 2007, 67, 616 https://doi.org/10.1158/0008-5472.CAN-06-1567
  8. Nishikawa, H.; Wakano, K.; Kitani, S. Biochem. Biophys. Res. Commun. 2007, 362, 504 https://doi.org/10.1016/j.bbrc.2007.08.015
  9. Bar-Shai, M.; Reznick, A. Z. Antioxid. Redox. Signal. 2006, 8, 639 https://doi.org/10.1089/ars.2006.8.639
  10. Ravagnan, L.; Gurbuxani, S.; Susin, S. A.; Maisse, C.; Daugas, E.; Zamzami, N.; Mak, T.; Jaattela, M.; Penninger, J. M.; Garrido, C.; Kroemer, G. Nat. Cell. Biol. 2001, 3, 839 https://doi.org/10.1038/ncb0901-839
  11. Gurbuxani, S.; Schmitt, E.; Cande, C.; Parcellier, A.; Hammann, A.; Daugas, E.; Kouranti, I.; Spahr, C.; Pance, A.; Kroemer, G.; Garrid, C. Oncogene 2003, 22, 6669 https://doi.org/10.1038/sj.onc.1206794
  12. Schmitt, E.; Parcellier, A.; Gurbuxani, S.; Cande, C.; Hammann, A.; Morales, M. C.; Hunt, C. R.; Dix, D. J.; Kroemer, R. T.; Giordanetto, F.; Jaattela, M.; Penninger, J. M.; Pance, A.; Kroemer, G.; Garrido, C. Cancer Res. 2003, 63, 8233
  13. Sriram, M.; Osipiuk, J.; Freeman, B.; Morimoto, R.; Joachimiak, A. Structure, 1997, 5, 403 https://doi.org/10.1016/S0969-2126(97)00197-4
  14. Lee, J. Y.; Lee, S. A.; Kim, Y. Bull. Korean Chem. Soc. 2007, 28, 941 https://doi.org/10.5012/bkcs.2007.28.6.941
  15. Lee, J. Y.; Baek, S.; Kim, Y. Bull. Korean Chem. Soc. 2007, 28, 379 https://doi.org/10.5012/bkcs.2007.28.3.379
  16. Morris, G. M.; Goodsell, D. S.; Halliday, R. S.; Huey, R.; Hart, W. E.; Belew, R. K.; Olson, A. J. J. Computational Chemistry. 1998, 19, 1639 https://doi.org/10.1002/(SICI)1096-987X(19981115)19:14<1639::AID-JCC10>3.0.CO;2-B
  17. Krammer, A.; Kirchhoff, P. D.; Venkatachalam, X. J. C. M.; Waldman, M. J. Mol. Graph. Model. 2005, 23, 395 https://doi.org/10.1016/j.jmgm.2004.11.007
  18. Verkhivker, G. M.; Bouzida, D.; Gehlhaar, D. K.; Rejto, P. A.; Arthurs, S.; Colson, A. B.; Freer, S. T.; Larson, V.; Lutyi, B. A.; Marrone, T.; Rose, P. W. Journal of Computer-Aided Molecular Design 2000, 14, 731 https://doi.org/10.1023/A:1008158231558
  19. Osipiuk, J.; Walsh, M. A.; Freeman, B. C.; Morimoto, R. I.; Joachimiak, A. Acta Crystallogr. D Biol. Crystallogr. 1999, 55, 1105 https://doi.org/10.1107/S0907444999002103
  20. Hatayama, T.; Asai, Y.; Wakatsuki, T.; Kitamura, T.; Imahara, H. J. Biochem. 1993, 114, 592 https://doi.org/10.1093/oxfordjournals.jbchem.a124222
  21. Yamamoto, N.; Smith, M. W.; Maki, A.; Berezesky, I. K.; Trump, B. F. Kidney Int. 1994, 45, 1093 https://doi.org/10.1038/ki.1994.146
  22. Resendez, E.; Jr., Ting, J.; Kim, S.; Wodden, S. K.; Lee, A. S. J. Cell. Biol. 1986, 103, 2145 https://doi.org/10.1083/jcb.103.6.2145
  23. Tillman, J. B.; Mote, P. L.; Walford, R. L.; Spindler, S. R. Gene 1995, 158, 225 https://doi.org/10.1016/0378-1119(95)00083-I
  24. Chen, L.; Zhang, H. Y. Molecules 2007, 12, 946 https://doi.org/10.3390/12050946
  25. O'Brien, M. C.; Flaherty, K. M.; McKay, D. B. J. Biol. Chem. 1996, 271, 15874 https://doi.org/10.1074/jbc.271.27.15874
  26. Leone, M.; Zhai, D.; Sareth, S.; Kitada, S.; Reed, J. C.; Pellecchia, M. Cancer Res. 2003, 63, 8118
  27. Khan, N.; Afaq, F.; Saleem, M.; Ahmad, N.; Mukhtar, H. Cancer Res. 2006, 66, 2500 https://doi.org/10.1158/0008-5472.CAN-05-3636
  28. Chung, J. Y.; Huang, C.; Meng, X.; Dong, Z.; Yang, C. S. Cancer Res. 1999, 59, 4610
  29. Rzadkowska-Bodalska, H.; Olechnowicz-Stepien, W. Pol. J. Pharmacol. Pharm. 1975, 27, 345

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