Quantitative structure-activity relationships (QSARs) for inhibitors and substrates of CYP2B enzymes: Importance of compound lipophilicity in explanation of potency differences

Journal of Enzyme Inhibition and Medicinal Chemistry

Volumn 25, Issue 5, 2010, Pages 679-684

  Lewis, David F V ^a   Ito, Yuko ^b   Lake, Brian G ^a  

^a UNIVERSITY OF SURREY   (United Kingdom)

^b YOKOHAMA CITY UNIVERSITY   (Japan)

Author keywords

Cytochromes P450; Enzyme Inhibition; Lipophilicity; QSARs

Indexed keywords

(N ALPHA METHYLBENZYL) 1 AMINOBENZOTRIAZOLE; 7 ETHOXYCOUMARIN; ALKYL GROUP; AMINE; BARBITURIC ACID DERIVATIVE; BENZOTRIAZOLE DERIVATIVE; BENZYL ISOTHIOCYANATE; BUTANAMINE; CYTOCHROME P450 2B; CYTOCHROME P450 2B1; CYTOCHROME P450 2B4; DECANAMINE; DERAMCICLANE FUMARATE; DODECANAMINE; ETHINYLESTRADIOL; ETHOXYCOUMARIN; HEPTANAMINE; HEXANAMINE; KETOCONAZOLE; METYRAPONE; OCTANAMINE; PENTANAMINE; PROPANAMINE; RETINOL; THIOTEPA; TICLOPIDINE; TRANYLCYPROMINE; TROGLITAZONE; UNCLASSIFIED DRUG; UNINDEXED DRUG; XANTHIC ACID DERIVATIVE;

ARTICLE; CRYSTAL STRUCTURE; DRUG POTENCY; ENZYME INHIBITION; LIPOPHILICITY; MOLECULAR MODEL; PRIORITY JOURNAL; PROTEIN EXPRESSION; QUANTITATIVE STRUCTURE ACTIVITY RELATION;

ALGORITHMS; ANIMALS; ARYL HYDROCARBON HYDROXYLASES; CATALYTIC DOMAIN; CYTOCHROME P-450 CYP2B1; CYTOCHROME P-450 ENZYME SYSTEM; ENZYME INHIBITORS; HUMANS; HYDROGEN BONDING; HYDROPHOBIC AND HYDROPHILIC INTERACTIONS; KINETICS; MODELS, MOLECULAR; MOLECULAR CONFORMATION; PROTEIN BINDING; QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP; RABBITS; RATS; XENOBIOTICS;

MAMMALIA; ORYCTOLAGUS CUNICULUS; RATTUS;

EID: 77956050452     PISSN: 14756366     EISSN: 14756374     Source Type: Journal    
DOI: 10.3109/14756360903514149     Document Type: Article

References (28)

1. Isin EM, Guengerich FP. Substrate binding to cytochromes P450. Anal Bioanal Chem 2008;392:1019-1030.
2. Lewis DFV. Guide to Cytochromes P450 Structure and Function. London:Taylor & Francis, 2001:76-117.
3. Nims RW, Lubet RA. The CYP2B subfamily. In: C Ioannides, ed. Cytochromes P450 - Metabolic and Toxicological Aspects. Boca Raton, Fl: CRC Press, 1996:135-160.
4. Turpeinen M, Raunio H and Pelkonen O. The functional role of CYP2B6 in human drug metabolism: substrates and inhibitors in vitro, in vivo and in silico. Curr Drug Metab 2006;7:705-714.
5. Halpert JR. Structural basis of selective cytochrome P450 inhibition. Ann Rev Pharmacol Toxicol 1995;35: 29-53.
6. Guengerich FP. (2005) Human cytochrome P450 enzymes. In: P.R. Ortiz de Montellano, ed. Cytochrome P450 Kluwer/Plenum, NY, 377-530.
7. Rendic S. Sumary of information on human CYP enzymes: human P450 metabolism data. Drug Metabol Rev 2002;34:83-448.
8. Roy K, Roy PP. Exploring QSAR and QAAR for inhibitors of cytochromes P4502A6 and 2A5 enzymes using GFA and G/PLS techniques. Eur J Med Chem 2009;44:1941-1951.
9. Roy PP, Roy K. QSAR studies of CYP2D6 inhibitor aryloxypropanolamines using 2D and 3D descriptors. Chem Biol Drug Des 2009;73:442-455.
10. Roy K, Roy PP. Comparative QSAR studies of CYP1A2 inhibitor flavonoids using 2D and 3D descriptors. Chem Biol Drug Des 2008;72:370-382.
11. Lewis DFV, Dickins M. Baseline lipophilicity relationships in human cytochromes P450 associated with drug metabolism. Drug Metabol Rev 2003;35:1-18.
12. Lewis DFV, Dickins M, Goldfarb PS. Molecular modelling of CYP2B6 based on homology with the CYP2C5 crystal structure: analysis of enzyme-substrate interactions. Drug Metab Drug Interact 2003; 19:115-135.
13. Lewis DFV, Lake BG, Ito Y, Anzenbacher P. Quantitative structure-activity relationships (QSARs) with cytochromes P450 2B (CYP2B) subfamily enzymes: the importance of lipophilicity for binding and metabolism. Drug Metab Drug Interact 2006;21:213-231.
14. Scott EE, White MA, He YA, Johnson EF, Stout CD, Halpert JR. Structure of mammalian cytochrome P450 2B4 complexed with 4-(4- chlorophenyl) imidazole at 1.9Ǻ resolution. Journal of Biol Chem 2004;279:27294-27301.
15. Jefcoate CR, Gaylor JL, and Calabrese R. Ligand interactions with cytochrome P450. 1. Binding of primary amines. Biochemistry, 8, 3455-3463.
16. Dickins M, Bridges JW. The relationship between the binding of 2-n-alkyl-benzimidazoles to rat heptic microsomal cytochrome P450 and the inhibition of mono-oxygenation. Biochem Pharmacol 1982;31:1315-1320.
17. Turpeinen M, Nieminen R, Juntunen T, Taavitsainen P, Raunio H Pelkonen O. Selective inhibition of CYP2B6-catalyzed bupropion hydroxylation in human liver microsomes in vitro. Drug Metab Dispos 2004;32:626-631.
18. Vermeir M, Boens N, Heirwegh KPM. Interaction of 7-n-alkoxycoumarins with cytochrome P4502 and their partitioning into liposomal membranes. Biochem J 1992;284:483-490.
19. Yih TD, van Rossum JM. KS values of some homologous series of barbiturates and the relationship with the lipophilicity and metabolic clearance. Biochem Pharmacol 1977;26:2117-2120.
20. Sangster J. Octanol-water partition coefficients of simple organic compounds. Journal of Phys Chem Ref Data 1989;18:1111-1229.
21. Hansch C, Leo A, Hoekman D. Exploring QSAR: Hydrophobic, Electronic and Steric Constants. Washington, American Chemical Society, 1995
22. van de Waterbeemd H, Mannhold, R. Lipophilicity descriptors for structure- property correlation studies: overview of experimental and theoretical methods and a benchmark of log P calculations. In: Pliska, B. Testa and H. van de Waterbeemd, eds. Lipophilicity in Drug Action and Toxicology V. VCH, Weinheim, 1996:401-418.
23. Lewis DFV, Jacobs MN, Dickins M. Compound lipophilicity for substrate binding to human P450s in drug metabolism. Drug DiscovToday 2004;9:530-537.
24. Lewis DFV, Ito Y, Goldfarb PS. (2008) Enzyme-substrate binding interaction energies and their application to the cytochrome P450 system. Current Computer-Aided Drug Design 4, 111-122.
25. Korhonen LE, Turpeinen M, Rahnasto M, Wittekindt C, Poso A, Pelkonen O, Raunio, H, Juvonen RO. (2007) New potent and selective cytochrome P450 2B6 (CYP2B6) inhibitors based on three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis. Br J Pharmacol 150, 932-942.
26. Fry JR, Hammond AH, Jassi KL, Bass AE, Bruce G, Laughton C, Shaw PN, Bylov IE, Kovalenko SM. (2004) Selectivity of 7-alkoxycoumarins as probe substrates for rat hepatic cytochrome P450 forms is influenced by the substitution pattern on the coumarin nucleus. Xenobiotica 34, 707-722.
27. Ekins S, Wrighton SA. (1999) The role of CYP2B6 in human xenobiotic metabolism. Drug Metabol Rev 31, 719-754.
28. Lewis DFV, Lake BG, Dickins M, Eddershaw PJ, Tarbit MH, Goldfarb PS. (1999) Molecular modelling of the phenobarbital-inducible P450 isoforms: CYP2B1, CYP2B4 and CYP2B6 by homology with the substratebound CYP102 crystal structure, and evaluation of CYP2B substrate binding affinity. Xenobiotica 29, 361-393.