title: Computational modeling of the potential interactions of the proteasome beta5 subunit and catechol-O-methyltransferase-resistant EGCG analogs.
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-Omicron-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 beta5 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.
authors.affiliation: The Prevention Program, Barbara Ann Karmanos Cancer Institute and Department of Pathology, School of Medicine, Wayne State University, Detroit, MI 48201, USA.
authors.forename: Jyoti
authors.initials: J
authors.lastname: Kanwar
authors.forename: Imthiyaz
authors.initials: I
authors.lastname: Mohammad
authors.forename: Huanjie
authors.initials: H
authors.lastname: Yang
authors.forename: Congde
authors.initials: C
authors.lastname: Huo
authors.forename: Tak Hang
authors.initials: TH
authors.lastname: Chan
authors.forename: Q Ping
authors.initials: QP
authors.lastname: Dou
mesh_terms: D002392:Catechin / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D065098:Catechol O-Methyltransferase Inhibitors; D003198:Computer Simulation; D005656:Fungal Proteins / Q000378:metabolism; D008958:Models, Molecular; D008968:Molecular Conformation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011485:Protein Binding; D025941:Protein Interaction Mapping; D013816:Thermodynamics
chemical_list: D065098:Catechol O-Methyltransferase Inhibitors; D005656:Fungal Proteins; D002392:Catechin; C045651:epigallocatechin gallate; D046988:Proteasome Endopeptidase Complex