High-throughput assays for promiscuous inhibitors
| Autor: | Brian Y. Feng, Anang A. Shelat, Brian K. Shoichet, Thompson N. Doman, R Kip Guy |
|---|---|
| Rok vydání: | 2005 |
| Předmět: |
chemistry.chemical_classification
Mechanism (biology) Drug discovery Systems biology Detergents Drug Evaluation Preclinical Computational Biology Cell Biology Computational biology Models Theoretical Biology Proteomics Enzyme chemistry Structural biology Biological target Drug Design Biological Assay Computer Simulation Enzyme Inhibitors Molecular Biology Functional genomics |
| Zdroj: | Nature Chemical Biology. 1:146-148 |
| ISSN: | 1552-4450 |
| DOI: | 10.1038/nchembio718 |
| Popis: | High-throughput screening (HTS) searches large libraries of chemical compounds for those that can modulate the activity of a particular biological target; it is the dominant technique used in early-stage drug discovery. A key problem in HTS is the prevalence of nonspecific or 'promiscuous' inhibitors. These molecules have peculiar properties, act on unrelated targets and can dominate the results from screening campaigns. Several explanations have been proposed to account for promiscuous inhibitors, including chemical reactivity, interference in assay read-out, high molecular flexibility and hydrophobicity. The diversity of these models reflects the apparently unrelated molecules whose behaviors they seek to explain. However, a single mechanism may explain the effects of many promiscuous inhibitors: some organic molecules form large colloid-like aggregates that sequester and thereby inhibit enzymes. Hits from HTS, leads for drug discovery and even several drugs appear to act through this mechanism at micromolar concentrations. Here, we report two rapid assays for detecting promiscuous aggregates that we tested against 1,030 'drug-like' molecules. The results from these assays were used to test two preliminary computational models of this phenomenon and as benchmarks to develop new models. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
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