Computational models for cytochrome P450: A predictive electronic model for aromatic oxidation and hydrogen atom abstraction

被引:109
作者
Jones, JP [1 ]
Mysinger, M
Korzekwa, KR
机构
[1] Washington State Univ, Dept Chem, Pullman, WA 99164 USA
[2] Camitro Corp, Menlo Pk, CA USA
关键词
D O I
10.1124/dmd.30.1.7
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Experimental observations suggest that electronic characteristics play a role in the rates of substrate oxidation for cytochrome P450 enzymes. For example, the tendency for oxidation of a certain functional group generally follows the relative stability of the radicals that are formed (e.g., N-dealkylation > O-dealkylation > 2 degrees carbon oxidation > 1 degrees carbon oxidation). In addition, results show that useful correlations between the rates of product formation can be developed using electronic models. In this article, we attempt to determine whether a combined computational model for aromatic and aliphatic hydroxylation can be developed. Toward this goal, we used a combination of experimental data and semiempirical molecular orbital calculations to predicted activation energies for aromatic and aliphatic hydroxylation. The resulting model extends the predictive capacity of our previous aliphatic hydroxylation model to include the second most important group of oxidations, aromatic hydroxylation. The combined model can account for about 83% of the variance in the data for the 20 compounds in the training set and has an error of about 0.7 kcal/mol.
引用
收藏
页码:7 / 12
页数:6
相关论文
共 31 条
[1]   METABOLIC SWITCHING IN CYTOCHROME-P-450CAM - DEUTERIUM-ISOTOPE EFFECTS ON REGIOSPECIFICITY AND THE MONOOXYGENASE OXIDASE RATIO [J].
ATKINS, WM ;
SLIGAR, SG .
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1987, 109 (12) :3754-3760
[2]   A novel approach to predicting P450 mediated drug metabolism. CYP2D6 catalyzed N-dealkylation reactions and qualitative metabolite predictions using a combined protein and pharmacophore model for CYP2D6 [J].
de Groot, MJ ;
Ackland, MJ ;
Horne, VA ;
Alex, AA ;
Jones, BC .
JOURNAL OF MEDICINAL CHEMISTRY, 1999, 42 (20) :4062-4070
[3]   METABOLITE PREDICTIONS FOR PARASUBSTITUTED ANISOLES BASED ON AB-INITIO COMPLETE ACTIVE SPACE SELF-CONSISTENT-FIELD CALCULATIONS [J].
DEGROOT, MJ ;
DENKELDER, GMDO ;
COMMANDEUR, JNM ;
VANLENTHE, JH ;
VERMEULEN, NPE .
CHEMICAL RESEARCH IN TOXICOLOGY, 1995, 8 (03) :437-443
[4]   THE DEVELOPMENT AND USE OF QUANTUM-MECHANICAL MOLECULAR-MODELS .76. AM1 - A NEW GENERAL-PURPOSE QUANTUM-MECHANICAL MOLECULAR-MODEL [J].
DEWAR, MJS ;
ZOEBISCH, EG ;
HEALY, EF ;
STEWART, JJP .
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1985, 107 (13) :3902-3909
[5]   Positional specificity of rabbit CYP4B1 for ω-hydroxylation of short-medium chain fatty acids and hydrocarbons [J].
Fisher, MB ;
Zheng, YM ;
Rettie, AE .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1998, 248 (02) :352-355
[6]   MODELING CYANIDE RELEASE FROM NITRILES - PREDICTION OF CYTOCHROME P450 MEDIATED ACUTE NITRILE TOXICITY [J].
GROGAN, J ;
DEVITO, SC ;
PEARLMAN, RS ;
KORZEKWA, KR .
CHEMICAL RESEARCH IN TOXICOLOGY, 1992, 5 (04) :548-552
[7]   MICROSOMAL HYDROXYLATION OF SPECIFICALLY DEUTERATED MONOSUBSTITUTED BENZENES - EVIDENCE FOR DIRECT AROMATIC HYDROXYLATION [J].
HANZLIK, RP ;
HOGBERG, K ;
JUDSON, CM .
BIOCHEMISTRY, 1984, 23 (13) :3048-3055
[8]  
HANZLIK RP, 1990, J ORG CHEM, V55, P3392
[9]   PENTAHALOETHANE-BASED CHLOROFLUOROCARBON SUBSTITUTES AND HALOTHANE - CORRELATION OF INVIVO HEPATIC PROTEIN TRIFLUOROACETYLATION AND URINARY TRIFLUOROACETIC-ACID EXCRETION WITH CALCULATED ENTHALPIES OF ACTIVATION [J].
HARRIS, JW ;
JONES, JP ;
MARTIN, JL ;
LAROSA, AC ;
OLSON, MJ ;
POHL, LR ;
ANDERS, MW .
CHEMICAL RESEARCH IN TOXICOLOGY, 1992, 5 (05) :720-725
[10]   Evaluation of cytochrome P450 mechanism and kinetics using kinetic deuterium isotope effects [J].
Higgins, L ;
Bennett, GA ;
Shimoji, M ;
Jones, JP .
BIOCHEMISTRY, 1998, 37 (19) :7039-7046