A 3D-QSAR model for CYP2D6 inhibition in the aryloxypropanolamine series

被引:24
作者
Vaz, RJ [1 ]
Nayeem, A [1 ]
Santone, K [1 ]
Chandrasena, G [1 ]
Gavai, AV [1 ]
机构
[1] Bristol Myers Squibb Co, Pharmaceut Res Inst, Princeton, NJ 08543 USA
关键词
CYP2D6; 3D-QSAR; aryloxypropanolamines;
D O I
10.1016/j.bmcl.2005.06.007
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
A comparative molecular similarity index analysis (CoMSiA) has been performed for cytochrome P450 2D6 inhibition on a series of aryloxypropatiolamines to determine the factors contributing to this activity. The model is in agreement with a CYP2D6 homology model constructed on the basis of the mammalian CYP2C5 crystal structure. The energy minimized conformations were generated using the systematic search methodology in Sybyl 6.7. The model not only elucidated the relationship between structure and biological activity but, more importantly, provided useful strategies to modulate CYP2D6 affinity in the aryloxypropanolamine series. (c) 2005 Elsevier Ltd. All rights reserved.
引用
收藏
页码:3816 / 3820
页数:5
相关论文
共 16 条
  • [1] [Anonymous], 3D QSAR DRUG DESIGN
  • [2] The design, preparation and SAR of novel small molecule sodium (Na+) channel blockers
    Ashwell, MA
    Lapierre, JM
    Kaplan, A
    Li, J
    Marr, C
    Yuan, J
    [J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2004, 14 (09) : 2025 - 2030
  • [3] Biller SA, 2004, BIOTECHNOL PHARM ASP, V1, P413
  • [4] COMPARATIVE MOLECULAR-FIELD ANALYSIS (COMFA) .1. EFFECT OF SHAPE ON BINDING OF STEROIDS TO CARRIER PROTEINS
    CRAMER, RD
    PATTERSON, DE
    BUNCE, JD
    [J]. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1988, 110 (18) : 5959 - 5967
  • [5] 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
    de Groot, MJ
    Ackland, MJ
    Horne, VA
    Alex, AA
    Jones, BC
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 1999, 42 (20) : 4062 - 4070
  • [6] Theoretical investigation of substrate specificity for cytochromes p450 IA2, p450 IID6 and p450 IIIA4
    De Rienzo, F
    Fanelli, F
    Menziani, MC
    De Benedetti, PG
    [J]. JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN, 2000, 14 (01) : 93 - 116
  • [7] ESSIOUX L, 2002, PHARMACOGENOMICS SEA, P57
  • [8] Role of glutamic acid 216 in cytochrome P450 2D6 substrate binding and catalysis
    Guengerich, FP
    Hanna, IH
    Martin, MV
    Gillam, EMJ
    [J]. BIOCHEMISTRY, 2003, 42 (05) : 1245 - 1253
  • [9] Diversity in the oxidation of substrates by cytochrome P450 2D6:: Lack of an obligatory role of aspartate 301 -: Substrate electrostatic bonding
    Guengerich, FP
    Miller, GP
    Hanna, IH
    Martin, MV
    Léger, S
    Black, C
    Chauret, N
    Silva, JM
    Trimble, LA
    Yergey, JA
    Nicoll-Griffith, DA
    [J]. BIOCHEMISTRY, 2002, 41 (36) : 11025 - 11034
  • [10] Inhibition of cytochrome P450 2D6: Structure-activity studies using a series of quinidine and quinine analogues
    Hutzler, JM
    Walker, GS
    Wienkers, LC
    [J]. CHEMICAL RESEARCH IN TOXICOLOGY, 2003, 16 (04) : 450 - 459