Optimization of 5-(2,6-dichlorophenyl)-3-hydroxy-2-mercaptocyclohex-2-enones as potent inhibitors of human lactate dehydrogenase
| Autor: | Binqing Wei, Erica VanderPorten, Mark Ultsch, Jason Boggs, Peter S. Dragovich, S. Sideris, Jinhua Chen, Huihui Zhang, Sharada Labadie, Qin Yue, Charles Z. Ding, Kirk Robarge, David Peterson, Shuguang Ma, Hans E. Purkey, Benjamin Fauber, HongXiu Ge, Aihe Zhou, Kwong Wah Lai, Qunh Ho, Shiva Malek, Xuying Zhang, Ivana Yen, Laura Corson, Charles Eigenbrot, Qing Xu, Laurent Salphati |
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| Rok vydání: | 2015 |
| Předmět: |
Gene isoform
Stereochemistry Lactate dehydrogenase A Clinical Biochemistry Pharmaceutical Science Crystallography X-Ray Biochemistry Madin Darby Canine Kidney Cells chemistry.chemical_compound Dogs Oxidoreductase Lactate dehydrogenase Drug Discovery Animals Humans Potency Glycolysis Enzyme Inhibitors education Molecular Biology chemistry.chemical_classification education.field_of_study L-Lactate Dehydrogenase Organic Chemistry Madin Darby canine kidney cell chemistry Molecular Medicine |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 25:75-82 |
| ISSN: | 0960-894X |
| Popis: | Optimization of 5-(2,6-dichlorophenyl)-3-hydroxy-2-mercaptocyclohex-2-enone using structure-based design strategies resulted in inhibitors with considerable improvement in biochemical potency against human lactate dehydrogenase A (LDHA). These potent inhibitors were typically selective for LDHA over LDHB isoform (4–10 fold) and other structurally related malate dehydrogenases, MDH1 and MDH2 (>500 fold). An X-ray crystal structure of enzymatically most potent molecule bound to LDHA revealed two additional interactions associated with enhanced biochemical potency. |
| Databáze: | OpenAIRE |
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