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Mining public-source databases for structure-activity relationships

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Modeling off-target effects has become a highly important and relevant component of the computational chemistry toolset. The presentation will describe a new contribution that seeks to allow the extraction of 3D-structure-activity relationships from public information starting from a chemical structure. Several public source databases such as PubChem [1] offering structure as well as activity information for a number of targets have been examined for their value in extracting useful structure-activity relationships (SARs). A Topomer search [2] of public-source databases using the structures of a set of 255 marketed drugs [3] as queries yielded sets of shape- and pharmacophore similar hits. SAR-tables were constructed by collecting hits around each query structure and for a particular reported activity. A new method: quantitative series enrichment analysis (QSEA) [4] was applied to these SAR-tables to capture trends and to transform these trends into 3D-QSAR models. Overall more than 400 SAR-tables with Topomer CoMFA models were found by extracting trends from the PubChem and ChemBank [5] database. The resulting models were able to highlight the structural details of certain off-target effects of marketed drugs even in those cases where the traditional structural similarity would conclude that no off-target effect would exist. This demonstrates the usefulness of the approach in modeling off-target effects.

References

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    [http://pubchem.ncbi.nlm.nih.gov]

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    Cramer RD: J Chem Inf Comp Sci. 2004, 44: 1221-1227.

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    Cleves AE, Jain AN: J Med Chem. 2006, 49: 2921-2938. 10.1021/jm051139t.

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    Wendt B, Cramer RD: J Comp Aided Mol Des. 2008, 22: 541-555. 10.1007/s10822-008-9195-6.

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    [http://chembank.broad.harvard.edu/]

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Correspondence to Bernd Wendt.

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Wendt, B., Bös, F. & Uhrig, U. Mining public-source databases for structure-activity relationships. J Cheminform 2, P4 (2010) doi:10.1186/1758-2946-2-S1-P4

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Keywords

  • Enrichment Analysis
  • Structural Detail
  • Public Information
  • Activity Information
  • Reported Activity