Bulletin of the Korean Chemical Society

Korean Chemical Society (대한화학회)
권호 표지
DOI QR코드

DOI QR Code

In Silico Screening of a Novel Inhibitor of β-Ketoacyl Acyl Carrier Protein Synthase I

  • Lee, Jee-Young (Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University) ;
  • Jeong, Ki-Woong (Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University) ;
  • Lee, Ju-Un (Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University) ;
  • Kang, Dong-Il (Department of Chemistry, Konkuk University) ;
  • Kim, Yang-Mee (Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University)
  • Received : 2011.01.31
  • Accepted : 2011.02.12
  • Published : 2011.05.20
Download PDF
⟨ Previous Next ⟩

Abstract

[ ${\beta}$ ]Ketoacyl acyl carrier protein synthase I (KAS I) is involved in the elongation of unsaturated fatty acids in bacterial fatty acid synthesis and a therapeutic target of designing novel antibiotics. In this study, we performed receptor-oriented pharmacophore-based in silico screening of E. coli KAS I (ecKAS I) with the aim of identifying novel inhibitors. We determined one pharmacophore map and selected 8 compounds as candidates ecKAS I inhibitors. We discovered one antimicrobial compound, YKAe1008, N-(3-pyridinyl) hexanamide, displaying minimal inhibitory concentration (MIC) values in the range of 128-256 ${\mu}g/mL$ against MRSA and VREF. YKAe1008 was subsequently assessed for binding to ecKAS I using saturation-transfer difference NMR spectroscopy. Further optimization of this compound will be carried out to improve its antimicrobial activity and membrane permeability against bacterial cell membrane.

Keywords

References

  1. Campbell, J. W.; Cronan, J. E., Jr. Annu. Rev. Microbiol. 2001, 55, 305. https://doi.org/10.1146/annurev.micro.55.1.305
  2. Khandekar, S. S.; Daines, R. A.; Lonsdale, J. T. Curr. Protein Pept. Sci. 2003, 4, 21. https://doi.org/10.2174/1389203033380377
  3. Lu, Y. J.; Zhang, Y. M.; Rock, C. O. Biochem. Cell Biol. 2004, 82,145. https://doi.org/10.1139/o03-076
  4. Marrakchi, H.; Zhang,Y. M.; Rock, C. O. Biochem. Soc. Trans. 2002, 30, 1050. https://doi.org/10.1042/bst0301050
  5. White, S. W.; Zheng, J.; Zhang, Y. M.; Rock, C. O. Annu. Rev. Biochem. 2005, 74, 791. https://doi.org/10.1146/annurev.biochem.74.082803.133524
  6. Heath, R. J.; Rock, C. O. J. Biol. Chem. 1996, 3, 10996.
  7. Heath, R. J.; Rock, C. O. Nat. Prod. Rep. 2002, 19, 581. https://doi.org/10.1039/b110221b
  8. Olsen, J. G.; Kadziola, A.; von Wettstein-Knowles, P.; Siggaard- Andersen, M.; Larsen, S. Structure 2001, 9, 233. https://doi.org/10.1016/S0969-2126(01)00583-4
  9. Price, A. C.; Choi, K. H.; Heath, R. J.; Li, Z.; White, S. W.; Rock, C. O. J. Biol. Chem. 2001, 276, 6551. https://doi.org/10.1074/jbc.M007101200
  10. von Wettstein-Knowles, P.; Olsen, J. G.; McGuire, K. A.; Henriksen, A. FEBS J. 2006, 273, 695. https://doi.org/10.1111/j.1742-4658.2005.05101.x
  11. Lee, J. Y.; Jeong, K. W.; Shin, S.; Lee, J. U.; Kim, Y. Bioorg. Med. Chem. 2009, 17, 5408. https://doi.org/10.1016/j.bmc.2009.06.059
  12. Jeong, K. W.; Lee, J. Y.; Kang, D. I.; Lee, J. U.; Shin, S. Y.; Kim, Y. J. Nat. Prod. 2009, 72, 719. https://doi.org/10.1021/np800698d
  13. Lee, J. Y.; Jeong, K. W.; Lee, J. U.; Kang, D. I.; Kim, Y. Bioorg. Med. Chem. 2009, 17, 1506. https://doi.org/10.1016/j.bmc.2009.01.004
  14. Murrall, N. W.; Davies, E. K. J. Chem. Inf. Comput. Sci. 1990, 30, 312. https://doi.org/10.1021/ci00067a016
  15. Hoffren, A. M.; Murray, C. M.; Hoffmann, R. D. Curr. Pharm. Des. 2001, 7, 547. https://doi.org/10.2174/1381612013397870
  16. Kirchhoff, P. D.; Brown, R.; Kahn, S.; Waldman, M.; Venkatachalam, C. M. J. Comp. Chem. 2001, 22, 993. https://doi.org/10.1002/jcc.1060
  17. Fisher, L. S.; Güner, O. F. J. Braz. Chem. Soc. 2002, 13, 777. https://doi.org/10.1590/S0103-50532002000600008
  18. MacLowry, J. D.; Jaqua, M. J.; Selepak, S. T. Appl. Microbiol. 1970, 20, 46.
  19. Smaill, F. Can. J. Gastroenterol. 2000, 14, 871. https://doi.org/10.1155/2000/382415
  20. Macnaughtan, M. A.; Kamar, M.; Alvarez-Manilla, G.; Venot, A.; Glushka, J.; Pierce, J. M.; Prestegard, J. H. J. Mol. Biol. 2007, 366, 1266. https://doi.org/10.1016/j.jmb.2006.12.015
  21. Mayer, M.; Meyer, B. J. Am. Chem. Soc. 2001, 123, 6108. https://doi.org/10.1021/ja0100120
  22. Venkatachalam, C. M.; Jiang, X.; Oldfield, T.; Waldman, M. J. Mol. Graph. Model. 2003, 21, 289. https://doi.org/10.1016/S1093-3263(02)00164-X
  23. Aparna, V.; Rambabu, G.; Panigrahi, S. K.; Sarma, J. A.; Desiraju, G. R. J. Chem. Inf. Model. 2005, 45, 725. https://doi.org/10.1021/ci049676u
  24. Veber, D. F.; Johnson, S. R.; Cheng, H. Y.; Smith, B. R.; Ward, K. W.; Kopple, K. D. J. Med. Chem. 2002, 45, 2615. https://doi.org/10.1021/jm020017n
  25. Jensen, B. F.; Refsgaardb, H. H. F.; Broc, R.; Brockhoff, P. B. QSAR Comb. Sci. 2005, 24, 449. https://doi.org/10.1002/qsar.200430928
  26. Ertl, P.; Rohde, B.; Selzer, P. J. Med. Chem. 2000, 43, 3714. https://doi.org/10.1021/jm000942e
  27. Irwin, J. J.; Shoichet, B. K. J. Chem. Inf. Model. 2005, 45, 177. https://doi.org/10.1021/ci049714+

Cited by

  1. vol.108, pp.5, 2018, https://doi.org/10.1111/mmi.13950