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    Please use this identifier to cite or link to this item: https://tkuir.lib.tku.edu.tw/dspace/handle/987654321/94004

    Title: EGFR與HER2抑制劑之間接與直接藥物設計
    Other Titles: Indirect and direct drug design of EGFR and HER2 inhibitors
    Authors: 張庭瑜;Chang, Ting-Yu
    Contributors: 淡江大學化學學系碩士班
    王伯昌;Wang, Bo-Cheng
    Keywords: 電腦輔助藥物設計;藥效基團模擬;分子對接模擬;酪胺酸激酶;Tyrosine kinase;EGFR;HER2;pharmacophore model;Docking;quinazoline
    Date: 2013
    Issue Date: 2014-01-23 13:46:45 (UTC+8)
    Abstract: 新藥的開發平均約需12-15年,其所耗費的金額相當可觀,隨著科技的進步,電腦模擬技術與藥物化學學科的結合,產生了電腦輔助藥物設計的新學門,其主要目的在於縮短藥物研發時間,而最終目標則是解決人類的疾病問題。
    Quantitative structure–activity relationship (QSAR) methods have been demonstrated as an effective tool in discovering novel lead compounds. And pharmacophore modeling is one of the 3D-QSAR methods which can used to approach for generate chemical features. This method is based on the 3D structure information of molecules, and has been successfully applied to the drug discovery.
    In an effort to establish a pharmacophore model for EGFR and HER2 inhibitor that could serve as a guide for the rational design of further potent and selective inhibitors. We have developed a quantitatively predictive chemical function-based pharmacophore model by using the HypoGen algorithm implemented in the Discovery Studio 2.1 software. The most optimal hypothesis for EGFR model consists of three features: one hydrophobic (HYD), one hydrogen bond acceptor (HBA), and two ring aromatic (RA) function. And for HER2 model consists of three features: one aromatic hydrophobic (aroHYD), one ring aromatic (RA), and two hydrogen bond acceptor (HBA) function. To further validate our design rationale, protein-ligand docking software was used to elucidated the intra-molecular interaction.
    According to the docking result with FMM, O3P, and quinazoline type inhibitors, the ligand position relative to the adjacent residues was further constructed. Therefore, the built pharmacophore model could help us to better understand how the substituents influence the activity and afford important information for both indirect and direct drug design.
    Appears in Collections:[Graduate Institute & Department of Chemistry] Thesis

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