Premium
Docking studies and model development of tea polyphenol proteasome inhibitors: Applications to rational drug design
Author(s) -
Smith David M.,
Daniel Kenyon G.,
Wang Zhigang,
Guida Wayne C.,
Chan TakHang,
Dou Q. Ping
Publication year - 2003
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.10504
Subject(s) - docking (animal) , chemistry , stereochemistry , proteasome , threonine , scissile bond , serine , active site , polyphenol , biochemistry , enzyme , medicine , nursing , antioxidant
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 β5‐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 Å. Furthermore, the A ring of (−)‐EGCG acts as a tyrosine mimic, binding to the hydrophobic S1 pocket of the β5‐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. Proteins 2003. © 2003 Wiley‐Liss, Inc.