本文選題：虛擬篩選 + 分布式計(jì)算��； 參考：《天津科技大學(xué)》2016年碩士論文

【摘要】：隨著計(jì)算技術(shù)的飛速發(fā)展和世界各地藥物的需要急劇增加,藥物研發(fā)已在過去60年里成為一個熱點(diǎn)問題。計(jì)算機(jī)輔助藥物設(shè)計(jì)(CADD)在藥物發(fā)現(xiàn)過程中起到了日益重要的作用。傳統(tǒng)的藥物篩選方法對于研究機(jī)構(gòu)和制藥公司來說難以負(fù)擔(dān)。所以,在計(jì)算機(jī)上的虛擬篩選經(jīng)常用于優(yōu)化高通量篩選實(shí)驗(yàn)。這可以使藥物研發(fā)的成本壓低到一較低的水平。分布式計(jì)算是指利用分布式系統(tǒng)來解決計(jì)算問題,其中的基本組件通信通過在分布式計(jì)算機(jī)傳遞消息來協(xié)調(diào)它們的行動。任務(wù)被分成許多子任務(wù),其中的每一個由一個或多個處理器解決。對于每個分布式作業(yè)有一個管理主機(jī)負(fù)責(zé)拆分工作,提交子任務(wù)和整合結(jié)果。依賴于程序,管理節(jié)點(diǎn)可以在本地主機(jī)上或在遠(yuǎn)程主機(jī)上運(yùn)行。硬件和軟件調(diào)試是在建立高通量虛擬篩選通道過程中重要的一環(huán),其中計(jì)算節(jié)點(diǎn)的兼容性,數(shù)據(jù)同步,合并文件和簡便的腳本都是重要的因素。適當(dāng)?shù)剡x擇打分函數(shù)也是我們方法驗(yàn)證的過程中遇到的問題。我們選擇了已知很多抑制劑的Aurora-A激酶和HDM-1內(nèi)酰胺酶等作為靶點(diǎn)來比較分析各種各樣的篩選方法如Ligandfit,GLIDE HTVS,GLIDE SP,GLIDE XP和Surflex,來說明基于分布式計(jì)算的虛擬篩選方法的合理性。Aurora-A,也被稱為絲氨酸/蘇氨酸-蛋白激酶6,是與細(xì)胞增殖和癌癥發(fā)展的調(diào)控相關(guān)的Aurora激酶家族的一個成員。HDM-1內(nèi)酰胺酶是是耐藥細(xì)菌針對內(nèi)酰胺類抗生素分泌的一類酶,使β—內(nèi)酰胺環(huán)裂解而被破壞,失去抗菌活性。本文利用具有660萬分子的類藥分子庫,針對NDM-1受體進(jìn)行虛擬篩選。體系的篩選速度和能力再次得到了肯定,得到了 13類421個分子。經(jīng)過目視檢查,選擇其中12個進(jìn)行購買與合成,并進(jìn)行了生物活性測試與結(jié)構(gòu)優(yōu)化改造,獲得了有較高抑制活性的候選化合物,通過對其進(jìn)一步的優(yōu)化與改造,闡述了衍生物結(jié)構(gòu)與活性之間的關(guān)系,以上研究將為藥物研發(fā)提供新方法和新思路。
[Abstract]:With the rapid development of computing technology and the rapid increase of drug demand all over the world, drug research and development has become a hot issue in the past 60 years. Computer aided drug design (CAD) plays an increasingly important role in drug discovery. Traditional drug screening methods are unaffordable for research institutions and pharmaceutical companies. Therefore, virtual filtering on computers is often used to optimize high-throughput screening experiments. This can reduce the cost of drug development to a lower level. Distributed computing is the use of distributed systems to solve computing problems, in which the basic components of communication through the transmission of messages in the distributed computer to coordinate their actions. Tasks are divided into subtasks, each of which is resolved by one or more processors. For each distributed job, a managed host is responsible for splitting, submitting subtasks and consolidating results. Depending on the program, the management node can run on a local host or on a remote host. Hardware and software debugging is an important part of the establishment of high-throughput virtual filtering channels, in which computing node compatibility, data synchronization, merging files and simple scripts are all important factors. Proper selection of scoring functions is also a problem in the process of our method verification. We selected Aurora-A kinase and HDM-1 lactamases of many known inhibitors as targets to compare and analyze various screening methods such as Ligandfitn GLIDE, GLIDE SPSPIDE, GLIDE XP and Surflex. to illustrate the reasonableness of the virtual screening method based on distributed computing. Aurora-A. Also known as serine / threonine protein kinase 6, a member of the Aurora kinase family associated with cell proliferation and cancer development, HDM-1 lactamases are a class of enzymes secreted by drug-resistant bacteria against lactam antibiotics. The 尾-lactam ring was destroyed by cleavage and lost antibacterial activity. In this paper, a drug-like library with 6.6 million molecules was used for virtual screening of NDM-1 receptors. The screening speed and ability of the system were confirmed again, and 421 molecules of 13 classes were obtained. After visual inspection, 12 of them were selected for purchase and synthesis, and the bioactivity test and structural optimization were carried out. Candidate compounds with high inhibitory activity were obtained, which were further optimized and modified. The relationship between the structure and activity of derivatives is expounded. The above research will provide new methods and new ideas for drug research and development.
【學(xué)位授予單位】：天津科技大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2016
【分類號】：R91;TP391.7

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