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

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 insig... Full description

Journal Title: Proceedings of the National Academy of Sciences of the United States of America 26 April 2011, Vol.108(17), pp.6817-6822
Main Author: Clemons, Paul A.
Other Authors: Wilson, J. Anthony , Dančík, Vlado , Muller, Sandrine , Carrinski, Hyman A. , Wagner, Bridget K. , Koehler, Angela N. , Schreiber, Stuart L. , Halpern, Jack
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: ISSN: 00278424
Link: https://www.jstor.org/stable/41242085
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recordid: jstor_archive_2341242085
title: Quantifying structure and performance diversity for sets of small molecules comprising small-molecule screening collections
format: Article
creator:
  • Clemons, Paul A.
  • Wilson, J. Anthony
  • Dančík, Vlado
  • Muller, Sandrine
  • Carrinski, Hyman A.
  • Wagner, Bridget K.
  • Koehler, Angela N.
  • Schreiber, Stuart L.
  • Halpern, Jack
subjects:
  • Physical sciences -- Physics -- Thermodynamics
  • Physical sciences -- Physics -- Microphysics
  • Information science -- Data products -- Datasets
  • Mathematics -- Mathematical analysis -- Principal components analysis
  • Physical sciences -- Chemistry -- Chemical elements
  • Physical sciences -- Physics -- Microphysics
  • Physical sciences -- Chemistry -- Chemoinformatics
  • Physical sciences -- Physics -- Thermodynamics
  • Physical sciences -- Chemistry -- Chemical compounds
  • Information science -- Data products -- Databases
ispartof: Proceedings of the National Academy of Sciences of the United States of America, 26 April 2011, Vol.108(17), pp.6817-6822
description: 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.
language: eng
source:
identifier: ISSN: 00278424
fulltext: fulltext
issn:
  • 0027-8424
  • 00278424
url: Link


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titleQuantifying structure and performance diversity for sets of small molecules comprising small-molecule screening collections
creatorClemons, Paul A. ; Wilson, J. Anthony ; Dančík, Vlado ; Muller, Sandrine ; Carrinski, Hyman A. ; Wagner, Bridget K. ; Koehler, Angela N. ; Schreiber, Stuart L. ; Halpern, Jack
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descriptionUsing 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.
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abstractUsing 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.
pubNational Academy of Sciences
doi10.1073/pnas.1015024108
eissn10916490
date2011-04-26