Journal article
The effects of nitrogen-heme-iron coordination on substrate affinities for cytochrome P450 2E1
Chemico-biological interactions, Vol.193(1), pp.50-56
08/15/2011
Handle:
https://hdl.handle.net/2376/104358
PMCID: PMC3129366
PMID: 21600194
Abstract
[Display omitted]
► 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. ► Predictive Model for CYP2E1 inhibition. ► New descriptor for nitrogen-iron coordination.
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 r2 value from 0.38 to 0.77.
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Details
- Title
- The effects of nitrogen-heme-iron coordination on substrate affinities for cytochrome P450 2E1
- Creators
- Jeffrey P Jones - Department of Chemistry, Washington State University, Pullman, Washington 99164-4630, USACarolyn A Joswig-Jones - Department of Chemistry, Washington State University, Pullman, Washington 99164-4630, USAMichelle Hebner - Department of Chemistry, Washington State University, Pullman, Washington 99164-4630, USAYuzhuo Chu - Department of Chemistry, Washington State University, Pullman, Washington 99164-4630, USADennis R Koop - Department of Physiology and Pharmacology, Oregon Health and Science University, Portland 97239-3098, USA
- Publication Details
- Chemico-biological interactions, Vol.193(1), pp.50-56
- Academic Unit
- Chemistry, Department of
- Publisher
- Elsevier Ireland Ltd
- Identifiers
- 99900546610601842
- Language
- English
- Resource Type
- Journal article