Using biological performance similarity to inform disaccharide library design

J Am Chem Soc. 2009 Apr 15;131(14):5075-83. doi: 10.1021/ja806583y.

Abstract

Designing better small-molecule discovery libraries requires having methods to assess the consequences of different synthesis decisions on the biological performance of resulting library members. Since we are particularly interested in how stereochemistry affects performance in biological assays, we prepared a disaccharide library containing systematic stereochemical variations, assayed the library for different biological effects, and developed methods to assess the similarity of performance between members across multiple assays. These methods allow us to ask which subsets of stereochemical features best predict similarity in patterns of biological performance between individual members and which features produce the greatest variation of outcomes. We anticipate that the data-analysis approach presented here can be generalized to other sets of biological assays and other chemical descriptors. Methods to assess which structural features of library members produce the greatest similarity in performance for a given set of biological assays should help prioritize synthesis decisions in second-generation library development targeting the underlying cell-biological processes. Methods to assess which structural features of library members produce the greatest variation in performance should help guide decisions about what synthetic methods need to be developed to make optimal small-molecule screening collections.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes / cytology
  • Adipocytes / metabolism
  • Animals
  • Cell Differentiation
  • Cells, Cultured
  • Combinatorial Chemistry Techniques / methods*
  • Disaccharides / chemical synthesis
  • Disaccharides / chemistry*
  • Disaccharides / metabolism*
  • Glycosylation
  • Mice
  • Mice, Knockout
  • Molecular Structure
  • Small Molecule Libraries / chemical synthesis
  • Small Molecule Libraries / chemistry*
  • Small Molecule Libraries / metabolism
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Disaccharides
  • Small Molecule Libraries