Docking studies and model development of tea polyphenol proteasome inhibitors: applications to rational drug design |
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Authors: | Smith David M Daniel Kenyon G Wang Zhigang Guida Wayne C Chan Tak-Hang Dou Q Ping |
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Institution: | Drug Discovery Program, H. Lee Moffitt Cancer Center and Research Institute, and Department of Biochemistry and Molecular Biology, College of Medicine, University of South Florida, Tampa, Florida, USA. |
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Abstract: | Previously, we demonstrated that natural and synthetic ester bond-containing green tea polyphenols were potent and specific non-peptide proteasome inhibitors. However, the molecular mechanism of inhibition is currently unknown. Here, we report that inhibition of the chymotrypsin activity of the 20S proteasome by (-)-epigallocatechin-3-gallate (EGCG) is time-dependent and irreversible, implicating acylation of the beta5-subunit's catalytic N-terminal threonine (Thr 1). This knowledge is used, along with in silico docking experiments, to aid in the understanding of binding and inhibition. On the basis of these docking experiments, we propose that (-)-EGCG binds the chymotrypsin site in an orientation and conformation that is suitable for a nucleophilic attack by Thr 1. Consistently, the distance from the electrophilic carbonyl carbon of (-)-EGCG to the hydroxyl group of Thr 1 was measured as 3.18 A. Furthermore, the A ring of (-)-EGCG acts as a tyrosine mimic, binding to the hydrophobic S1 pocket of the beta5-subunit. In the process, the (-)-EGCG scissile bond may become strained, which could lower the activation energy for attack by the hydroxyl group of Thr 1. This model is validated by comparison of predicted and actual activities of several EGCG analogs, either naturally occurring, previously synthesized, or rationally synthesized. |
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Keywords: | 20S proteasome β5‐subunit chymotrypsin‐like activity EGCG green tea organic synthesis computation drug discovery |
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