6PNO
Human GSTO1-1 complexed with 2-chloro-N-(4-chloro-3-(N-isopropylsulfamoyl)phenyl)acetamide
Summary for 6PNO
| Entry DOI | 10.2210/pdb6pno/pdb |
| Descriptor | Glutathione S-transferase omega-1, 2-chloro-N-{4-chloro-3-[(propan-2-yl)sulfamoyl]phenyl}acetamide, L(+)-TARTARIC ACID, ... (5 entities in total) |
| Functional Keywords | glutathione transferase, inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 28232.13 |
| Authors | Oakley, A.J. (deposition date: 2019-07-02, release date: 2019-07-24, Last modification date: 2024-11-20) |
| Primary citation | Xie, Y.,Tummala, P.,Oakley, A.J.,Deora, G.S.,Nakano, Y.,Rooke, M.,Cuellar, M.E.,Strasser, J.M.,Dahlin, J.L.,Walters, M.A.,Casarotto, M.G.,Board, P.G.,Baell, J.B. Development of Benzenesulfonamide Derivatives as Potent Glutathione Transferase Omega-1 Inhibitors. J.Med.Chem., 63:2894-2914, 2020 Cited by PubMed Abstract: Glutathione transferase omega-1 (GSTO1-1) is an enzyme whose function supports the activation of interleukin (IL)-1β and IL-18 that are implicated in a variety of inflammatory disease states for which small-molecule inhibitors are sought. The potent reactivity of the active-site cysteine has resulted in reported inhibitors that act by covalent labeling. In this study, structure-activity relationship (SAR) elaboration of the reported GSTO1-1 inhibitor was undertaken. Compounds were evaluated for inhibitory activity toward purified recombinant GSTO1-1 and for indicators of target engagement in cell-based assays. As covalent inhibitors, the / values of selected compounds were determined, as well as in vivo pharmacokinetics analysis. Cocrystal structures of key novel compounds in complex with GSTO1-1 were also solved. This study represents the first application of a biochemical assay for GSTO1-1 to determine / values for tested inhibitors and the most extensive set of cell-based data for a GSTO1-1 inhibitor SAR series reported to date. Our research culminated in the discovery of , which we propose as the preferred biochemical tool to interrogate cellular responses to GSTO1-1 inhibition. PubMed: 32105470DOI: 10.1021/acs.jmedchem.9b01391 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.82 Å) |
Structure validation
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