Computational modeling of the potential interactions of the proteasome β5 subunit and catechol-Ο-methyltransferase-resistant EGCG analogs

  • Authors:
    • Jyoti Kanwar
    • Imthiyaz Mohammad
    • Huanjie Yang
    • Congde Huo
    • Tak Hang Chan
    • Q. Ping Dou
  • View Affiliations

  • Published online on: August 1, 2010     https://doi.org/10.3892/ijmm_00000454
  • Pages: 209-215
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Abstract

(-)-Epigallocatechin gallate [(-)-EGCG] has been implicated in cancer chemoprevention and has been shown as an inhibitor of tumor proteasomal chymotrypsin-like activity in vitro and in vivo. However, EGCG is subjected to rapid biotransforming modifications such as methylation by catechol-Ο-methyltransferase (COMT) that limits its action. We recently reported that structure 7, an EGCG analog which should be resistant to COMT-mediated methylation and inactivation in cells, was able to inhibit the activity of purified 20S proteasome and cellular 26S proteasome. However, the involved molecular mechanism is unknown. Herein, we applied computational solution to understand the possible interaction between EGCG analogs including structure 7 and the proteasome β5 subunit which is responsible for the chymotrypsin-like activity. We report that the ester carbonyls at C2 and C3 carbon atoms may be the active sites for nucleophilic attack in structure 7 and 5. Equally spaced carbon atoms in COMT-resistant structure 7 give more stable conformation and lower docked free energy than other EGCG analogs. The absence of a second gallate group in structure 16 and 21 significantly decreases the ability to inhibit the proteasome.

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August 2010
Volume 26 Issue 2

Print ISSN: 1107-3756
Online ISSN:1791-244X

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APA
Kanwar, J., Mohammad, I., Yang, H., Huo, C., Chan, T.H., & Dou, Q.P. (2010). Computational modeling of the potential interactions of the proteasome β5 subunit and catechol-Ο-methyltransferase-resistant EGCG analogs . International Journal of Molecular Medicine, 26, 209-215. https://doi.org/10.3892/ijmm_00000454
MLA
Kanwar, J., Mohammad, I., Yang, H., Huo, C., Chan, T. H., Dou, Q. P."Computational modeling of the potential interactions of the proteasome β5 subunit and catechol-Ο-methyltransferase-resistant EGCG analogs ". International Journal of Molecular Medicine 26.2 (2010): 209-215.
Chicago
Kanwar, J., Mohammad, I., Yang, H., Huo, C., Chan, T. H., Dou, Q. P."Computational modeling of the potential interactions of the proteasome β5 subunit and catechol-Ο-methyltransferase-resistant EGCG analogs ". International Journal of Molecular Medicine 26, no. 2 (2010): 209-215. https://doi.org/10.3892/ijmm_00000454