English  |  正體中文  |  简体中文  |  Items with full text/Total items : 12145/12927 (94%)
Visitors : 847963      Online Users : 658
RC Version 6.0 © Powered By DSPACE, MIT. Enhanced by NTU Library IR team.
Scope Tips:
  • please add "double quotation mark" for query phrases to get precise results
  • please goto advance search for comprehansive author search
    •  Adv. Search
    Home ‧ Login ‧ Upload ‧ Help ‧ About ‧ Administer Goto mobile version


    Please use this identifier to cite or link to this item: http://ir.nhri.org.tw/handle/3990099045/6882


    Title: 3D-QSAR-assisted drug design: Identification of a potent quinazoline-based aurora kinase inhibitor
    Authors: Ke, YY;Shiao, HY;Hsu, YC;Chu, CY;Wang, WC;Lee, YC;Lin, WH;Chen, CH;Hsu, JTA;Chang, CW;Lin, CW;Yeh, TK;Chao, YS;Coumar, MS;Hsieh, HP
    Contributors: Institute of Biotechnology and Pharmaceutical Research
    Abstract: We describe the 3D-QSAR-assisted design of an Aurora kinase A inhibitor with improved physicochemical properties, in vitro activity, and in vivo pharmacokinetic profiles over those of the initial lead. Three different 3D-QSAR models were built and validated by using a set of 66 pyrazole (Model I) and furanopyrimidine (Model II) compounds with IC50 values toward Aurora kinase A ranging from 33 nM to 10.5 μM. The best 3D-QSAR model, Model III, constructed with 24 training set compounds from both series, showed robustness (r2CV=0.54 and 0.52 for CoMFA and CoMSIA, respectively) and superior predictive capacity for 42 test set compounds (R2pred=0.52 and 0.67, CoMFA and CoMSIA). Superimposition of CoMFA and CoMSIA Model III over the crystal structure of Aurora kinase A suggests the potential to improve the activity of the ligands by decreasing the steric clash with Val147 and Leu139 and by increasing hydrophobic contact with Leu139 and Gly216 residues in the solvent-exposed region of the enzyme. Based on these suggestions, the rational redesign of furanopyrimidine 24 (clog P=7.41; Aurora A IC50=43 nM; HCT-116 IC50=400 nM) led to the identification of quinazoline 67 (clog P=5.28; Aurora A IC50=25 nM; HCT-116 IC50=23 nM). Rat in vivo pharmacokinetic studies showed that 67 has better systemic exposure after i.v. administration than 24, and holds potential for further development.
    Date: 2013-01
    Relation: ChemMedChem. 2013 Jan;8(1):136-148.
    Link to: http://dx.doi.org/10.1002/cmdc.201200464
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=1860-7179&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000314172100017
    Cited Times(Scopus): http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=84871641453
    Appears in Collections:[謝興邦] 期刊論文
    [趙宇生(2002-2013)] 期刊論文
    [葉燈光] 期刊論文
    [徐祖安] 期刊論文
    [王文傑] 期刊論文

    Files in This Item:

    File Description SizeFormat
    WIL2012120102.pdf1466KbAdobe PDF676View/Open


    All items in NHRI are protected by copyright, with all rights reserved.

    Related Items in TAIR

    DSpace Software Copyright © 2002-2004  MIT &  Hewlett-Packard  /   Enhanced by   NTU Library IR team Copyright ©   - Feedback