Discovery of glutathione S-transferase inhibitors using dynamic combinatorial chemistry.
Protein-directed dynamic combinatorial chemistry (DCC) relies on reversible chemical reactions that can function under the near-physiological conditions required by the biological target. Few classes of reaction have so far proven effective at generating dynamic combinatorial libraries (DCLs) under such constraints. In this study, we establish the conjugate addition of thiols to enones as a reaction well-suited for the synthesis of dynamic combinatorial libraries (DCLs) directed by the active site of the enzyme glutathione S-transferase (GST). The reaction is fast, freely reversible at basic pH, and easily interfaced with the protein, which is a target for the design of inhibitors in cancer therapy and the treatment of parasitic diseases such as schistosomiasis. We have synthesized DCLs based on glutathione (GSH, 1) and the enone ethacrynic acid, 2a. By varying either set of components, we can choose to probe either the GSH binding region ("G site") or the adjacent hydrophobic acceptor binding region ("H site") of the GST active site. In both cases the strongest binding DCL components are identified due to molecular amplification by GST which, in the latter system, leads to the identification of two new inhibitors for the GST enzyme.
Shi
Baolu
B
School of Chemistry, University of Edinburgh, The King's Buildings, West Mains Road, Edinburgh EH9 3JJ, United Kingdom.
Stevenson
Ross
R
Campopiano
Dominic J
DJ
Greaney
Michael F
MF
D001665:Binding Sites; D020650:Combinatorial Chemistry Techniques / Q000379:methods*; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D004976:Ethacrynic Acid / Q000737:chemistry; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors / Q000737:chemistry*; D007659:Ketones / Q000737:chemistry* / Q000494:pharmacology; D015394:Molecular Structure; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D007659:Ketones; D005982:Glutathione Transferase; D004976:Ethacrynic Acid