期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 107, 期 44, 页码 18787-18792出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1012741107
关键词
chemical diversity; cheminformatics; natural products; small-molecule microarrays; small-molecule probes
资金
- NIGMS [P50-GM069721]
- National Institutes of Health RoadMap [P20-HG003895]
- National Cancer Institute [N01-CO-12400]
Using a diverse collection of small molecules generated from a variety of sources, we measured protein-binding activities of each individual compound against each of 100 diverse (sequence-unrelated) proteins using small-molecule microarrays. We also analyzed structural features, including complexity, of the small molecules. We found that compounds from different sources (commercial, academic, natural) have different protein-binding behaviors and that these behaviors correlate with general trends in stereochemical and shape descriptors for these compound collections. Increasing the content of sp(3)-hybridized and stereogenic atoms relative to compounds from commercial sources, which comprise the majority of current screening collections, improved binding selectivity and frequency. The results suggest structural features that synthetic chemists can target when synthesizing screening collections for biological discovery. Because binding proteins selectively can be a key feature of high-value probes and drugs, synthesizing compounds having features identified in this study may result in improved performance of screening collections.
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