Matt presented this poster at ISSX in September 2010.
A number of methods have been developed for the prediction of regioselectivity of metabolism by the major drug metabolising isoforms of Cytochrome P450 [1,2,3]. However, while valuable, predicting the relative proportion of metabolite formation at different sites on a molecule is only a partial solution to designing more stable molecules. Valuable additional information comes from predicting a measure of the vulnerability of each site to metabolism. Such a measurement is the site lability, as calculated by StarDrop. This important factor in determining the overall rate of metabolism, when combined with other descriptors relating to substrate affinity, can provide good predictive models of in vitro metabolic rate which can, in turn, guide design of compounds with improved stability.
We will demonstrate this with a case study, targeting a fast follower for a compound that has problems with poor oral bioavailability and short and variable half-life in man.
 V.S. Gopaul et. al. (2009) Drug Metab. Rev. 41(s3) pp. 187-196 (abstract 242)
 P. Rydberg et. al. (2010) ACS Med. Chem. Lett. 1(3) pp 96–100
 M. Hennemann et. al. (2009) ChemMedChem 4(3) p. 657-69
A copy of this poster as available as a PDF.