TY - JOUR T1 - Structure-Based Identification of Novel Human γ-Glutamylcysteine Synthetase Inhibitors JF - Molecular Pharmacology JO - Mol Pharmacol SP - 1140 LP - 1147 DO - 10.1124/mol.106.024778 VL - 71 IS - 4 AU - David Hamilton AU - Jian Hui Wu AU - Gerald Batist Y1 - 2007/04/01 UR - http://molpharm.aspetjournals.org/content/71/4/1140.abstract N2 - Glutathione depletion represents a potentially important strategy to sensitize tumors to cytotoxic drugs. l-Buthionine-(R,S)-sulfoximine (l-BSO) has been studied in both preclinical and early clinical trials, but limitation on its access has led to a search for alternatives. Using a 3D molecular model of human γ-glutamylcysteine synthetase (γ-GCSH), the major subunit of the rate-limiting GSH synthetic enzyme, we virtually screened the National Cancer Institute chemical database to identify compounds that could bind to and potentially inhibit γ-GCSH. We identified 51 test chemicals, all with structures very distinct from l-BSO. We subjected these compounds to biological assays measuring γ-GCSH inhibition and glutathione (GSH) depletion. Among 10 novel γ -GCS inhibitors identified, 4 compounds depleted glutathione in cells, and 2 with related structures sensitized tumor cells to melphalan treatment. This work validates the use of model-based database mining and identified inhibitors of γ-GCSH with novel chemical structures. The American Society for Pharmacology and Experimental Therapeutics ER -