The effects of nitrogen-heme-iron coordination on substrate affinities for cytochrome P450 2E1

Jeffrey P. Jones, Carolyn A. Joswig-Jones, Michelle Hebner, Yuzhuo Chu, Dennis R. Koop

Research output: Contribution to journalArticlepeer-review

17 Scopus citations


A descriptor based computational model was developed for cytochrome P450 2E1 (CYP2E1) based on inhibition constants determined for inhibition of chlorzoxazone, or 4-nitrophenol, metabolism. An empirical descriptor for type II binding was developed and tested for a series of CYP2E1 inhibitors. Inhibition constants where measured for 51 different compounds. A fast 2-dimensional predictive model was developed based on 40 compounds, and tested on 8 compounds of diverse structure. The trained model (n = 40) had an r2 value of 0.76 and an RMSE of 0.48. The correlation between the predicted and actual pKi values of the test set of compounds not included in the model gives an r2 value of 0.78. The features that described binding include heme coordination (type II binding), molecular volume, octanol/water partition coefficient, solvent accessible surface area, and the sum of the atomic polarizabilities. The heme coordination parameter assigns an integer between 0 and 6 depending on structure, and is a new descriptor, based on simple quantum chemical calculations with correction for steric effects. The type II binding parameter was found to be important in obtaining a good correlation between predicted and experimental inhibition constants increasing the r 2 value from 0.38 to 0.77.

Original languageEnglish (US)
Pages (from-to)50-56
Number of pages7
JournalChemico-Biological Interactions
Issue number1
StatePublished - Aug 15 2011


  • 2E1
  • CYP
  • Nitrogen-iron coordination
  • P450
  • QSAR
  • Type II binding

ASJC Scopus subject areas

  • Toxicology


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