Structural and Chemical Basis for Anticancer Activity of a Series of β-Tubulin Ligands: Molecular Modeling and 3D QSAR Studies

被引:12
作者
Salum, Livia B. [1 ]
Dias, Luiz C. [2 ]
Andricopulo, Adriano D. [1 ]
机构
[1] Univ Sao Paulo, Inst Fis Sao Carlos, Ctr Biotecnol Mol Estruct, Lab Quim Med & Computac, BR-13560970 Sao Carlos, SP, Brazil
[2] Univ Estadual Campinas, Inst Quim, BR-13083970 Campinas, SP, Brazil
基金
巴西圣保罗研究基金会;
关键词
cancer; drug design; discodermolide; microtubule; beta-tubulin; BIOLOGICAL EVALUATION; SIMPLIFIED ANALOGS; FIELD ANALYSIS; BINDING; DESIGN; TAXOL; DISCODERMOLIDE; MICROTUBULES; DOCKING; (+)-DISCODERMOLIDE;
D O I
10.1590/S0103-50532009000400013
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
An important approach to cancer therapy is the design of small molecule modulators that interfere with microtubule dynamics through their specific binding to the beta-subunit of tubulin. In the present work, comparative molecular field analysis (CoMFA) studies were conducted on a series of discodermolide analogs with antimitotic properties. Significant correlation coefficients were obtained (CoMFA((i)), q(2) = 0.68, r(2) = 0.94; CoMFA((ii)), q(2) = 0.63, r(2) = 0.91), indicating the good internal and external consistency of the models generated using two independent structural alignment strategies. The models were externally validated employing a test set, and the predicted values were in good agreement with the experimental results. The final QSAR models and the 3D contour maps provided important insights into the chemical and structural basis involved in the molecular recognition process of this family of discodermolide analogs, and should be useful for the design of new specific beta-tubulin modulators with potent anticancer activity.
引用
收藏
页码:693 / 703
页数:11
相关论文
共 49 条
  • [1] Three-dimensional quantitative structure-activity relationships for a large series of potent antitubercular agents
    Andrade, Carolina Horta
    Salum, Livia de Barros
    Mesquita Pasqualoto, Kerly Fernanda
    Ferreira, Elizabeth Igne
    Andricopulo, Adriano Defini
    [J]. LETTERS IN DRUG DESIGN & DISCOVERY, 2008, 5 (06) : 377 - 387
  • [2] Structure-activity relationships for the design of small-molecule inhibitors
    Andricopulo, AD
    Montanari, CA
    [J]. MINI-REVIEWS IN MEDICINAL CHEMISTRY, 2005, 5 (06) : 585 - 593
  • [3] BOLLAG DM, 1995, CANCER RES, V55, P2325
  • [4] Design, synthesis and cytotoxicity of 7-deoxy aryl discodermolide analogues
    Burlingame, MA
    Shaw, SJ
    Sundermann, KF
    Zhang, D
    Petryka, J
    Mendoza, E
    Liu, FH
    Myles, DC
    LaMarche, MJ
    Hirose, T
    Freeze, BS
    Smith, AB
    [J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2004, 14 (09) : 2335 - 2338
  • [5] Classical and hologram QSAR studies on a series of tacrine derivatives as butyryleholinesterase inhibitors
    Castilho, M. S.
    Guido, R. V. C.
    Andricopulo, A. D.
    [J]. LETTERS IN DRUG DESIGN & DISCOVERY, 2007, 4 (02) : 106 - 113
  • [6] Two- and three-dimensional quantitative structure-activity relationships for a series of purine nucleoside phosphorylase inhibitors
    Castilho, MS
    Postigo, MP
    de Paula, CBV
    Montanari, CA
    Oliva, G
    Andricopulo, AD
    [J]. BIOORGANIC & MEDICINAL CHEMISTRY, 2006, 14 (02) : 516 - 527
  • [7] VALIDATION OF THE GENERAL-PURPOSE TRIPOS 5.2 FORCE-FIELD
    CLARK, M
    CRAMER, RD
    VANOPDENBOSCH, N
    [J]. JOURNAL OF COMPUTATIONAL CHEMISTRY, 1989, 10 (08) : 982 - 1012
  • [8] Cramer R D 3rd, 1989, Prog Clin Biol Res, V291, P161
  • [9] 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
  • [10] CoMFA, HQSAR and molecular docking studies of butitaxel analogues with β-tubulin
    Cunningham, SL
    Cunningham, AR
    Day, BW
    [J]. JOURNAL OF MOLECULAR MODELING, 2005, 11 (01) : 48 - 54