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

Kanwar,Jyoti; Mohammad,Imthiyaz; Yang,Huanjie; Huo,Congde; Chan,Tak Hang; Dou,Q. Ping

doi:10.3892/ijmm_00000454

August 2010 Volume 26 Issue 2

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August 2010 Volume 26 Issue 2

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Article

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 / Copyright

Affiliations: The Prevention Program, Barbara Ann Karmanos Cancer Institute and Department of Pathology, School of Medicine, Wayne State University, Detroit, MI 48201, USA
Pages: 209-215
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Published online on: August 1, 2010

https://doi.org/10.3892/ijmm_00000454
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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.

Journals

International Journal of Molecular Medicine

International Journal of Oncology

Molecular Medicine Reports

Oncology Reports

Experimental and Therapeutic Medicine

Oncology Letters

Biomedical Reports

Molecular and Clinical Oncology

World Academy of Sciences Journal

International Journal of Functional Nutrition

International Journal of Epigenetics

Medicine International

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

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Abstract

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