A review of the use of in silico methods to predict the chemistry of molecular initiating events related to drug toxicity

Expert Opin Drug Metab Toxicol. 2011 Dec;7(12):1481-95. doi: 10.1517/17425255.2011.629186. Epub 2011 Oct 28.


Introduction: Drug toxicity pathways can be extremely complex and difficult to fully understand. However, understanding specific parts of the pathway may be simpler. Every toxicity pathway starts with a molecular initiating event (MIE). If an MIE is well understood then it becomes possible to predict which compounds can partake in that particular MIE using in silico techniques.

Areas covered: This review aims to describe how the use of structural alerts and the measurement/calculation of certain physicochemical properties can identify chemicals with a given MIE. For example, structural alerts can be used to identify chemicals able to form a covalent bond with a biological macromolecule. How chemistry-related MIEs relate to toxicity end points, such as hepatotoxicity, is also discussed.

Expert opinion: It is emphasised that predicting that a compound can cause an MIE is not a direct prediction of toxicity. Predicting whether a compound will be toxic requires a comparison with similar compounds which cause the same MIE and that are associated with known toxicological data. It is possible to form categories of compounds that are all thought to act via the same MIE and then use read-across within the category to make a toxicity prediction.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Chemical Phenomena
  • Chemistry, Pharmaceutical / methods
  • Endpoint Determination / methods*
  • Molecular Structure
  • Pharmaceutical Preparations / analysis*
  • Quantitative Structure-Activity Relationship
  • Risk Assessment / methods
  • Toxicity Tests / methods*
  • Toxicology / methods*


  • Pharmaceutical Preparations