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, 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.
Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, MA 02142, USA. pclemons@broadinstitute.org
Paul A
PA
Clemons
Nicole E
NE
Bodycombe
Hyman A
HA
Carrinski
J Anthony
JA
Wilson
Alykhan F
AF
Shamji
Bridget K
BK
Wagner
Angela N
AN
Koehler
Stuart L
SL
Schreiber
D055808:Drug Discovery; D008962:Models, Theoretical; D040081:Protein Array Analysis / Q000379:methods*; D011485:Protein Binding; D011506:Proteins / Q000737:chemistry*
D011506:Proteins