Plague Research Today is a free monthly online journal that collates and summarizes the latest research about Plague, including details on bubonic plague, yersinia pestis, infection, types, treatment.

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

Metz JT, Huth JR, Hajduk PJ

Pharmaceutical Discovery Division, Abbott Laboratories, R46Y, AP-10, 100 Abbott Park Road, Abbott Park, IL, 60064-3500, USA, philip.hajduk@abbott.com.

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.

Published 9 March 2007 in J Comput Aided Mol Des, 21(1): 139-44.
Full-text of this article is available online (may require subscription).

© 2005-2008 Plague Research Today. All Rights Reserved.