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

Proc Natl Acad Sci U S A
Authors
Keywords
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. 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 Publication
2010
Journal
Proc Natl Acad Sci U S A
Volume
107
Issue
44
Pages
18787-92
Date Published
2010 Nov 02
ISSN
1091-6490
DOI
10.1073/pnas.1012741107
PubMed ID
20956335
PubMed Central ID
PMC2973913
Links
Grant list
P50-GM069721 / GM / NIGMS NIH HHS / United States
P20-HG003895 / HG / NHGRI NIH HHS / United States
Howard Hughes Medical Institute / United States
P50 GM069721 / GM / NIGMS NIH HHS / United States
N01CO12400 / CA / NCI NIH HHS / United States
N01-CO-12400 / CO / NCI NIH HHS / United States
P20 HG003895 / HG / NHGRI NIH HHS / United States