1,193
Views
17
CrossRef citations to date
0
Altmetric
Research Article

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

, &
Pages 679-684 | Received 26 Mar 2009, Accepted 27 Nov 2009, Published online: 25 Jan 2010

References

  • Isin EM, Guengerich FP. Substrate binding to cytochromes P450. Anal Bioanal Chem 2008;392:1019–1030.
  • Lewis DFV. Guide to Cytochromes P450 Structure and Function. London:Taylor & Francis, 2001:76–117.
  • 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.
  • 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.
  • Halpert JR. Structural basis of selective cytochrome P450 inhibition. Ann Rev Pharmacol Toxicol 1995;35: 29–53.
  • Guengerich FP. (2005) Human cytochrome P450 enzymes. In: P.R. Ortiz de Montellano, ed. Cytochrome P450 Kluwer/Plenum, NY, 377–530.
  • Rendic S. Sumary of information on human CYP enzymes: human P450 metabolism data. Drug Metabol Rev 2002;34:83–448.
  • 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.
  • Roy PP, Roy K. QSAR studies of CYP2D6 inhibitor aryloxypropanolamines using 2D and 3D descriptors. Chem Biol Drug Des 2009;73:442–455.
  • Roy K, Roy PP. Comparative QSAR studies of CYP1A2 inhibitor flavonoids using 2D and 3D descriptors. Chem Biol Drug Des 2008;72:370–382.
  • Lewis DFV, Dickins M. Baseline lipophilicity relationships in human cytochromes P450 associated with drug metabolism. Drug Metabol Rev 2003;35:1–18.
  • 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.
  • 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.
  • 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 1.9å´ resolution. Journal of Biol Chem 2004;279:27294–27301.
  • Jefcoate CR, Gaylor JL, and Calabrese R. Ligand interactions with cytochrome P450. 1. Binding of primary amines. Biochemistry, 8, 3455–3463.
  • 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.
  • 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.
  • 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.
  • 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.
  • Sangster J. Octanol-water partition coefficients of simple organic compounds. Journal of Phys Chem Ref Data 1989;18:1111–1229.
  • Hansch C, Leo A, Hoekman D. Exploring QSAR: Hydrophobic, Electronic and Steric Constants. Washington, American Chemical Society, 1995
  • 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.
  • Lewis DFV, Jacobs MN, Dickins M. Compound lipophilicity for substrate binding to human P450s in drug metabolism. Drug DiscovToday 2004;9:530–537.
  • 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.
  • 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.
  • 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.
  • Ekins S, Wrighton SA. (1999) The role of CYP2B6 in human xenobiotic metabolism. Drug Metabol Rev 31, 719–754.
  • 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 substrate-bound CYP102 crystal structure, and evaluation of CYP2B substrate binding affinity. Xenobiotica 29, 361–393.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.