Small molecules of different origins have distinct distributions of structural complexity that correlate with protein-binding profiles
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...
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Proceedings of the National Academy of Sciences
2018
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| Online Access: | http://hdl.handle.net/1721.1/116671 https://orcid.org/0000-0002-3772-8156 |
| _version_ | 1826202107357691904 |
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| author | Clemons, P. A. Bodycombe, N. E. Carrinski, H. A. Wilson, J. A. Wagner, B. K. Schreiber, S. L. Shamji, Alykhan Koehler, Angela Nicole |
| author2 | Harvard University--MIT Division of Health Sciences and Technology |
| author_facet | Harvard University--MIT Division of Health Sciences and Technology Clemons, P. A. Bodycombe, N. E. Carrinski, H. A. Wilson, J. A. Wagner, B. K. Schreiber, S. L. Shamji, Alykhan Koehler, Angela Nicole |
| author_sort | Clemons, P. A. |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T12:01:59Z |
| format | Article |
| id | mit-1721.1/116671 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T12:01:59Z |
| publishDate | 2018 |
| publisher | Proceedings of the National Academy of Sciences |
| record_format | dspace |
| spelling | mit-1721.1/1166712022-09-27T23:40:03Z Small molecules of different origins have distinct distributions of structural complexity that correlate with protein-binding profiles Clemons, P. A. Bodycombe, N. E. Carrinski, H. A. Wilson, J. A. Wagner, B. K. Schreiber, S. L. Shamji, Alykhan Koehler, Angela Nicole Harvard University--MIT Division of Health Sciences and Technology Massachusetts Institute of Technology. Department of Biological Engineering Shamji, Alykhan Koehler, Angela Nicole 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. National Institute of General Medical Sciences (U.S.) (P50-GM069721) National Institutes of Health (U.S.) (P20-HG003895) National Cancer Institute (U.S.) (N01-CO-12400) 2018-06-27T19:46:32Z 2018-06-27T19:46:32Z 2010-11 2010-08 2018-06-18T19:05:50Z Article http://purl.org/eprint/type/JournalArticle 0027-8424 1091-6490 http://hdl.handle.net/1721.1/116671 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 https://orcid.org/0000-0002-3772-8156 http://dx.doi.org/10.1073/pnas.1012741107 Proceedings of the National Academy of Sciences 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. application/pdf Proceedings of the National Academy of Sciences PNAS |
| spellingShingle | Clemons, P. A. Bodycombe, N. E. Carrinski, H. A. Wilson, J. A. Wagner, B. K. Schreiber, S. L. Shamji, Alykhan Koehler, Angela Nicole Small molecules of different origins have distinct distributions of structural complexity that correlate with protein-binding profiles |
| title | Small molecules of different origins have distinct distributions of structural complexity that correlate with protein-binding profiles |
| title_full | Small molecules of different origins have distinct distributions of structural complexity that correlate with protein-binding profiles |
| title_fullStr | Small molecules of different origins have distinct distributions of structural complexity that correlate with protein-binding profiles |
| title_full_unstemmed | Small molecules of different origins have distinct distributions of structural complexity that correlate with protein-binding profiles |
| title_short | Small molecules of different origins have distinct distributions of structural complexity that correlate with protein-binding profiles |
| title_sort | small molecules of different origins have distinct distributions of structural complexity that correlate with protein binding profiles |
| url | http://hdl.handle.net/1721.1/116671 https://orcid.org/0000-0002-3772-8156 |
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