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SHAO Xin, YI Qianying, YANG Chunlei. Discovery of novel EphB4 inhibitors based on pharmacophore modeling and virtual screening techniques[J]. Journal of China Pharmaceutical University, 2016, 47(1): 38-47. DOI: 10.11665/j.issn.1000-5048.20160105
Citation: SHAO Xin, YI Qianying, YANG Chunlei. Discovery of novel EphB4 inhibitors based on pharmacophore modeling and virtual screening techniques[J]. Journal of China Pharmaceutical University, 2016, 47(1): 38-47. DOI: 10.11665/j.issn.1000-5048.20160105
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Discovery of novel EphB4 inhibitors based on pharmacophore modeling and virtual screening techniques

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  • The objective of this paper was to discover new potent inhibitors against EphB4 for cancer therapy via computer-aided drug design strategies including 3D-QSAR modeling, virtual screening and molecular docking. The first step was to generate pharmacophore models based on Catalyst/HypoGen algorithm. The best model, Hypo1, had the highest Correl value(0. 96), the lowest RMS value(0. 89), the closest total cost(101. 26)to fixed cost(89. 20), and the best Δcost(89. 14). Subsequently, Hypo1 was subjected to test set validation and Fischer′s randomization verification and was then used as a 3D query to screen database. In order to further narrow the number of hits, drug-likeness screening and molecular docking techniques were applied. Finally, 23 novel molecules with diverse scaffolds were selected as possible candidates against EphB4 for further studies based on predicted activity analysis, docking scores, and binding mode analysis.
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  • [1]
    Zhang XG,Yao LB.The signal transduction pathway and function of Eph receptors and its ligands[J].Prog Biochem Biophy(生物化学和生物物理学进展),2001,28(4):498-501.
    [2]
    Sun JF,Liu HJ,Li C.Relationship between expressions of EphB4 with angiogenesis in human colorectal carcinoma[J].J Frontier Med(医药前沿),2013,5(21):250-255.
    [3]
    Bardelle C,Cross D,Davenport S,et al.Inhibitors of the tyrosine kinase EphB4.Part 1:structure-based design and optimization of a series of 2,4-bis-anilinopyrimidines[J].Bioorg Med Chem Lett,2008,18(2):2776-2780.
    [4]
    Bardelle C,Coleman T,Cross D,et al.Inhibitors of the tyrosine kinase EphB4.Part 2:structure-based discovery and optimisation of 3,5-bis substituted anilinopyrimidines[J].Bioorg Med Chem Lett,2008,18(5):5717-5721.
    [5]
    Barlaam B, Ducray R, Read J, et al. Inhibitors of the tyrosine kinase EphB4.Part 4:discovery and optimization of a benzylic alcohol series[J].Bioorg Med Chem Lett,2011,21(22):2207-2211.
    [6]
    Lafleur K,Huang D,Zhou T,et al.Structure-based optimization of potent and selective inhibitors of the tyrosine kinase erythropoietin producing human hepatocellular carcinoma receptor B4(EphB4)[J].J Med Chem,2009,52(6):6433-6446.
    [7]
    Lafleur K,Dong J,Huang D,et al.Optimization of inhibitors of the tyrosine kinase EphB4.2.Cellular potency improvement and binding mode validation by X-ray crystallography[J].J Med Chem,2013,56(1):84-96.
    [8]
    Miyazaki Y,Nakano M,Sato M,et al.Design and effective synthesis of novel templates,3,7-diphenyl-4-amino-thieno and furo-[3,2-c]pyridines as protein kinase inhibitors and in vitro evaluation targeting angiogenetic kinases[J].Bioorg Med Chem Lett,2007,17(2):250-254.
    [9]
    Mitchell SA,Danca MD,Blomgren PA,et al.Imidazo[1,2-a]pyrazine diaryl ureas:inhibitors of the receptor tyrosine kinase EphB4[J].Bioorg Med Chem Lett,2009,19(6):6991-6995.
    [10]
    Fischer R.The Principle of Experimentation,Illustrated by a Psycho-Physical Experiment,in the Design of Experiments[M].New York:Hafner Publishing Company,1966:129-153.
    [11]
    Walters WP,Murcko MA.Prediction of ‘drug-likeness’[J].Adv Drug Delivery Rev,2002,54(2):255-271.
    [12]
    Cheng A, Merz KM Jr. Prediction of aqueous solubility of a diverse set of compounds using quantitative structure-property relationships[J].J Med Chem,2003,46(3):3572-3580.
    [13]
    Vermunt JE,Magidson J.Latent GOLD 5.0 Upgrade Manual[M].Belmont:Statistical Innovations Inc.,2013:540-555.
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