【摘要】：分子對接方法是基于結(jié)構(gòu)的藥物設(shè)計的有力工具之一,隨著越來越多的蛋白質(zhì)晶體結(jié)構(gòu)被解析出來,分子對接方法也得到越來越多推廣與運(yùn)用。同時,現(xiàn)有分子對接方法存在的問題也被相繼提出來,比如構(gòu)象搜索不充分、打分函數(shù)不夠精確、溶劑效應(yīng)和蛋白質(zhì)的柔性處理有限等。其中,如何合理處理蛋白質(zhì)的柔性是分子對接方法研究中難點問題之一。鑒于此,本文以蛋白質(zhì)與配體小分子結(jié)合前后的構(gòu)象變化尺度為分子柔性尺度評判標(biāo)準(zhǔn),通過統(tǒng)計分析,對現(xiàn)已解析出晶體結(jié)構(gòu)的蛋白質(zhì)按照柔性尺度進(jìn)行聚類,為考慮蛋白質(zhì)柔性的藥物設(shè)計提供了數(shù)據(jù)支持。此外,本文選擇部分關(guān)鍵殘基柔性的蛋白質(zhì)作為測試集,對本課題組前期發(fā)展的iFitDock和兩個主流分子對接方法(AutoDock和Induced-Fit Docking)展開了測試評價,結(jié)果表明,iFitDock對配體和蛋白質(zhì)活性構(gòu)象的預(yù)測精度均顯著高于其他分子對接方法,為考慮蛋白質(zhì)柔性的分子對接方法的發(fā)展和完善提供了理論依據(jù)。 作為一類重要的翻譯后修飾酶,法尼基轉(zhuǎn)移酶(Farnesyltransferase, FTase)對Ras蛋白的膜定位和生物功能的正常運(yùn)作起著至關(guān)重要的作用,是重要的癌癥治療靶標(biāo)。本課題組在前期的研究中,通過虛擬篩選方法,發(fā)現(xiàn)了若干靶向法尼基轉(zhuǎn)移酶的小分子抑制劑。本文針對其中的酰胺聯(lián)苯醚類抑制劑,采用分子對接方法,對其展開構(gòu)效關(guān)系研究,并依此提出該類化合物的結(jié)構(gòu)修飾策略,結(jié)合化學(xué)合成及生物測試,獲得了一系列高活性的酰胺聯(lián)苯醚類抑制劑。
[Abstract]:Molecular docking method is one of the powerful tools for structure-based drug design. As more and more protein crystal structures are resolved, molecular docking methods are more and more widely used. At the same time, the existing problems of molecular docking methods have been put forward one after another, such as insufficient conformation search, inaccuracy of scoring function, solvent effect and limited flexibility of protein treatment and so on. Among them, how to deal with the flexibility of protein is one of the difficult problems in molecular docking. In view of this, the conformational change scale before and after the binding of protein with small ligand molecules is taken as the criterion of molecular flexibility scale. Through statistical analysis, the proteins with crystal structure are clustered according to flexible scale. It provides data support for drug design considering protein flexibility. In addition, some flexible proteins of key residues were selected as test sets to test and evaluate iFitDock and two mainstream molecular docking methods (AutoDock and Induced-Fit Docking) developed by our team. The results show that, The prediction accuracy of ligands and protein active conformation by iFitDock is significantly higher than that of other molecular docking methods, which provides a theoretical basis for the development and improvement of molecular docking methods considering protein flexibility. As an important class of post-translational modifiers, farinotransferase (Farnesyltransferase, FTase) plays an important role in the membrane localization and biological function of Ras proteins, and is an important target for cancer therapy. In our previous study, we found some small molecular inhibitors targeting farinyltransferase by virtual screening method. In this paper, the molecular docking method was used to study the unfolded structure-activity relationship of Amidobenzene Ether inhibitors, and the structural modification strategy, chemical synthesis and bioassay of the compounds were proposed. A series of high activity Amidobenzene Ether inhibitors were obtained.
【學(xué)位授予單位】：華東理工大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2014
【分類號】：R91-39

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相關(guān)期刊論文 前1條

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本文編號：2363608