1. High throughput screening identifies ATP-competitive inhibitors of the NLRP1 inflammasome.
- Author
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Harris PA, Duraiswami C, Fisher DT, Fornwald J, Hoffman SJ, Hofmann G, Jiang M, Lehr R, McCormick PM, Nickels L, Schwartz B, Wu Z, Zhang G, Marquis RW, Bertin J, and Gough PJ
- Subjects
- Adaptor Proteins, Signal Transducing genetics, Adaptor Proteins, Signal Transducing metabolism, Adenosine Triphosphate metabolism, Apoptosis Regulatory Proteins genetics, Apoptosis Regulatory Proteins metabolism, Binding Sites, Binding, Competitive, High-Throughput Screening Assays, Humans, Molecular Docking Simulation, NLR Proteins, Protein Binding, Protein Structure, Tertiary, Pyrazoles chemistry, Pyrazoles metabolism, Recombinant Fusion Proteins biosynthesis, Recombinant Fusion Proteins chemistry, Recombinant Fusion Proteins isolation & purification, Structure-Activity Relationship, Adaptor Proteins, Signal Transducing antagonists & inhibitors, Adenosine Triphosphate chemistry, Apoptosis Regulatory Proteins antagonists & inhibitors, Inflammasomes metabolism
- Abstract
Nod-like receptors (NLRs) are cytoplasmic pattern recognition receptors that are promising targets for the development of anti-inflammatory therapeutics. Drug discovery efforts targeting NLRs have been hampered by their inherent tendency to form aggregates making protein generation and the development of screening assays very challenging. Herein we report the results of an HTS screen of NLR family member NLRP1 (NLR family, pyrin domain-containing 1) which was achieved through the large scale generation of recombinant GST-His-Thrombin-NLRP1 protein. The screen led to the identification of a diverse set of ATP competitive inhibitors with micromolar potencies. Activity of these hits was confirmed in a FP binding assay, and two homology models were employed to predict the possible binding mode of the leading series and facilitate further lead-optimization. These results highlight a promising strategy for the identification of inhibitors of NLR family members which are rapidly emerging as key drivers of inflammation in human disease., (Copyright © 2015 Elsevier Ltd. All rights reserved.) more...
- Published
- 2015
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