Small molecules of different origins have distinct distributions of structural complexity that correlate with protein-binding profiles
By Paul A. Clemons, Nicole E. Bodycombe, Hyman A. Carrinski, J. A. Wilson, Alykhan F. Shamji, B. Wagner, A. Koehler, Stefan Schreiber. 2010
293 citations recorded by the source corpus.
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 sp3-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.
Subfields: Computational Theory and Mathematics, Molecular Biology
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In Molecular Biology
Citations in the corpus
- Systems Pharmacology: Network Analysis to Identify Multiscale Mechanisms of Drug Action (2012, background): “The potential of false positives may be decreased through the application of orthogonal experimental techniques such as high-content screening (74), in vitro ADMET (75), medicinal chemistry techniques (76, 77), binding screens (78), and gene regulation (79).”