Small molecules of different origins have distinct distributions of structural complexity that correlate with protein-binding profiles
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Author(s)
Clemons, P. A.
Bodycombe, N. E.
Carrinski, H. A.
Wilson, J. A.
Wagner, B. K.
Schreiber, S. L.
Shamji, Alykhan
Koehler, Angela Nicole
Date Issued
November 2010
Journal
Proceedings of the National Academy of Sciences
Publisher
Proceedings of the National Academy of Sciences
Citation
Clemons, P. A., et al. “Small Molecules of Different Origins Have Distinct Distributions of Structural Complexity That Correlate with Protein-Binding Profiles.” Proceedings of the National Academy of Sciences, vol. 107, no. 44, Nov. 2010, pp. 18787–92. © 2018 National Academy of Sciences
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Final published version
Abstract
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. Wefound 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.
MIT Department
Harvard University--MIT Division of Health Sciences and Technology
Massachusetts Institute of Technology. Department of Biological Engineering
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Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.
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DOI of Published Version
https://doi.org/10.1073/pnas.1012741107
