Abstract
An objective of chemical genetics is to understand the relationships between the structures of small molecules and their phenotypic effects in intact living systems. We present here the results of a global analysis of a molecular descriptor space constructed using structural descriptors of an aryl 1, 3-dioxane-based diversity-oriented synthesis-derived library containing structural biasing elements directed at inhibiting protein deacetylases. Using principal component analysis and three-dimensional visualization, we generated metric space maps with morphological features contributed by different diversity positions within the library. Filtering these maps using phenotypic descriptors derived from measurements of small-molecule activities in an array of cell-based assays revealed different densities of biological activity within specific subspaces. These results provide evidence that certain structural features may be important for conferring potency and selectivity on deacetylase inhibitors with respect to tubulin and histone acetylation. Moreover, these results highlight an example of the importance of usin g functional measures to assess molecular diversity. Similar analyses of other chemical spaces and activity classes promise to facilitate the development of chemical genetics.
Keywords: deacetylase inhibitors, chemical genetics, molecular descriptors, principal components analysis
Combinatorial Chemistry & High Throughput Screening
Title: Mapping Chemical Space Using Molecular Descriptors and Chemical Genetics: Deacetylase Inhibitors
Volume: 7 Issue: 7
Author(s): Stephen J. Haggarty, Paul A. Clemons, Jason C. Wong and Stuart L. Schreiber
Affiliation:
Keywords: deacetylase inhibitors, chemical genetics, molecular descriptors, principal components analysis
Abstract: An objective of chemical genetics is to understand the relationships between the structures of small molecules and their phenotypic effects in intact living systems. We present here the results of a global analysis of a molecular descriptor space constructed using structural descriptors of an aryl 1, 3-dioxane-based diversity-oriented synthesis-derived library containing structural biasing elements directed at inhibiting protein deacetylases. Using principal component analysis and three-dimensional visualization, we generated metric space maps with morphological features contributed by different diversity positions within the library. Filtering these maps using phenotypic descriptors derived from measurements of small-molecule activities in an array of cell-based assays revealed different densities of biological activity within specific subspaces. These results provide evidence that certain structural features may be important for conferring potency and selectivity on deacetylase inhibitors with respect to tubulin and histone acetylation. Moreover, these results highlight an example of the importance of usin g functional measures to assess molecular diversity. Similar analyses of other chemical spaces and activity classes promise to facilitate the development of chemical genetics.
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Cite this article as:
Haggarty J. Stephen, Clemons A. Paul, Wong C. Jason and Schreiber L. Stuart, Mapping Chemical Space Using Molecular Descriptors and Chemical Genetics: Deacetylase Inhibitors, Combinatorial Chemistry & High Throughput Screening 2004; 7 (7) . https://dx.doi.org/10.2174/1386207043328319
DOI https://dx.doi.org/10.2174/1386207043328319 |
Print ISSN 1386-2073 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5402 |
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