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Quantifying structure and performance diversity for sets of small molecules comprising small-molecule screening collections.

Abstract：

:Using a diverse collection of small molecules we recently found that compound sets from different sources (commercial; academic; natural) have different protein-binding behaviors, and these behaviors correlate with trends in stereochemical complexity for these compound sets. These results lend insight into structural features that synthetic chemists might target when synthesizing screening collections for biological discovery. We report extensive characterization of structural properties and diversity of biological performance for these compounds and expand comparative analyses to include physicochemical properties and three-dimensional shapes of predicted conformers. The results highlight additional similarities and differences between the sets, but also the dependence of such comparisons on the choice of molecular descriptors. Using a protein-binding dataset, we introduce an information-theoretic measure to assess diversity of performance with a constraint on specificity. Rather than relying on finding individual active compounds, this measure allows rational judgment of compound subsets as groups. We also apply this measure to publicly available data from ChemBank for the same compound sets across a diverse group of functional assays. We find that performance diversity of compound sets is relatively stable across a range of property values as judged by this measure, both in protein-binding studies and functional assays. Because building screening collections with improved performance depends on efficient use of synthetic organic chemistry resources, these studies illustrate an important quantitative framework to help prioritize choices made in building such collections.

journal_name

Proc Natl Acad Sci U S A

journal_title

Proceedings of the National Academy of Sciences of the United States of America

authors

Clemons PA,Wilson JA,Dančík V,Muller S,Carrinski HA,Wagner BK,Koehler AN,Schreiber SL

doi

10.1073/pnas.1015024108

subject

Has Abstract

pub_date

2011-04-26 00:00:00

pages

6817-22

issue

eissn

0027-8424

issn

1091-6490

pii

1015024108

journal_volume

108

pub_type

杂志文章

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Quantifying structure and performance diversity for sets of small molecules comprising small-molecule screening collections.