Journal of Computer-Aided Molecular Design

, Volume 21, Issue 1–3, pp 139–144 | Cite as

Enhancement of chemical rules for predicting compound reactivity towards protein thiol groups

  • James T. Metz
  • Jeffrey R. Huth
  • Philip J. Hajduk
Original Paper


Non-specific chemical modification of protein thiol groups continues to be a significant source of false positive hits from high-throughput screening campaigns and can even plague certain protein targets and chemical series well into lead optimization. While experimental tools exist to assess the risk and promiscuity associated with the chemical reactivity of existing compounds, computational tools are desired that can reliably identify substructures that are associated with chemical reactivity to aid in triage of HTS hit lists, external compound purchases, and library design. Here we describe a Bayesian classification model derived from more than 8,800 compounds that have been experimentally assessed for their potential to covalently modify protein targets. The resulting model can be implemented in the large-scale assessment of compound libraries for purchase or design. In addition, the individual substructures identified as highly reactive in the model can be used as look-up tables to guide chemists during hit-to-lead and lead optimization campaigns.


Bayesian classifier Compound reactivity ALARM-NMR Pipeline pilot 



JTM would like to thank the support staff at SciTegic for many helpful discussions, suggestions, and corrections to Pipeline Pilot protocols.

Supplementary material

10822_2007_9109_MOESM1_ESM.xls (231 kb)
ESM2 (xls 231 kb)


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Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • James T. Metz
    • 1
  • Jeffrey R. Huth
    • 1
  • Philip J. Hajduk
    • 1
  1. 1.Pharmaceutical Discovery DivisionAbbott LaboratoriesAbbott ParkUSA

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