Scientific Publications

Small molecules of different origins have distinct distributions of structural complexity that correlate with protein-binding profiles.

Publication TypeJournal Article
AuthorsClemons, PA, Bodycombe NE, Carrinski HA, Wilson JA, Shamji AF, Wagner BK, Koehler AN, and Schreiber SL
AbstractUsing 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.
Year of Publication2010
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue44
Pages18787-92
Date Published (YYYY/MM/DD)2010/11/02
ISSN Number0027-8424
DOI10.1073/pnas.1012741107
PubMedhttp://www.ncbi.nlm.nih.gov/pubmed/20956335?dopt=Abstract