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苯并噻唑類似物抑制T3151野生和突變的Bcr-Abl激酶的計算機輔助藥物設計研究

時間:2019-04-20 14:30來源:畢業論文
運用比較分子力場分析方法(CoMFA)和比較分子相似性指數分析法(CoMSIA)對一系列新型苯并噻唑類似物的結構參數和pIC50值進行分析,以42個分子結構和pIC50值已知的苯并噻唑類似物為訓

摘要融合蛋白(ABL),它是一種能夠不斷激活酪氨酸激酶的一種致活酶,然而苯并噻唑可以成為很好的ABL抑制劑。本文運用比較分子力場分析方法(CoMFA)和比較分子相似性指數分析法(CoMSIA)對一系列新型苯并噻唑類似物的結構參數和pIC50值進行分析,以42個分子結構和pIC50值已知的苯并噻唑類似物為訓練集, 用三維定量構效關系(3D-QSAR)方法建立了預測模型,采用抽一法(leave one out,LOO) 檢驗了預測模型的可信性,接著用一個由12個新型苯并噻唑類似物組成的測試集進一步驗證預測模型的預測能力,用交叉驗證系數q2和相關系數R2的值來證實3D-QSAR 預測模型是否有良好的預測能力。通過從CoMFA、CoMSIA等勢圖的分析結果,設計了一系列新的化合物,發現了從理論上可以得到有更高抑制活性的化合物。研究結果表明我所建立的3D-QSAR模型在統計學上具有明確、良好的預測能力。34710
    此外,本文基于一系列已知化學結構的苯并噻唑類似物,構建了其三維藥效團模型。挑選出構效關系最好的藥效團模型,進行計算。
畢業論文關鍵詞:三維定量構效關系(3D-QSAR);苯并噻唑類似物;pIC50值;CoMFA;CoMSIA
Design of Benzothiazole analogue for restraining Wild type and T135I and breakpoint cluster region-ablelson
Abstract
Fusion protein (ABL), it is a capable of continuous activation of tyrosine kinase A induced enzyme activity. However, benzene and thiazole analogs can become very good ABL inhibitors.
This paper uses comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) of a series of novel benzothiazole analogues of the structure parameters and pIC50 value were analyzed, with 64 molecular structure and pIC50 value of the known benzothiazole analogues for the training set, with three-dimensional quantitative structure-activity the relationship between (3D-QSAR) method for predicting model is established, using a method of extraction (leave one out, LOO) to test the credibility of prediction model, followed by a model consisting of 12 benzothiazole analogues of the test set to validate model predictive ability, using cross validation coefficient Q2 and the correlation coefficient of R2 to confirm whether 3D-QSAR value prediction model has a good predictive ability. From the results of potential map analysis of CoMSIA and CoMFA, a series of new compounds were designed, and the compounds were found to have higher inhibitory activity.. The results show that the 3D-QSAR model is clearly and well predicted by statistics..
源`自*六)維[論*文'網www.aftnzs.live

In addition, in this paper, a series of known chemical structure of benzothiazole based analogue, establishes the three-dimensional pharmacophore model. The best model of the model was selected, and the reliability of the model was verified by the test set and Fischer random verification method..
Key words:Three-dimensional quantitative structure-activity relationship (3D-QSAR);new Benzothiazole analogs;pIC50 value;CoMFA;CoMSIA
目錄
第一章 緒論    1
1.1 研究的背景與目的    1
1.2 研究現狀和進展    1
1.3 主要研究內容    3
第二章 理論原理及計算方法    5
2.1 SYBYL軟件簡介    5
2.2 三維定量構效關系(3D-QSAR)的介紹及其基本原理    5
2.3 研究方法概述    6
2.3.1 化合物活性構象的確定    6
2.3.2 分子疊合    6
2.3.3 CoMFA和CoMSIA簡介    6
2.4 研究方案    7
2.4.1 數據集的收集    7
2.4.2 模型構建的準備工作及分子疊合,建立training(訓練集),test(測試集)    8
2.4.3 CoMFA模型的建立    8 苯并噻唑類似物抑制T3151野生和突變的Bcr-Abl激酶的計算機輔助藥物設計研究:http://www.aftnzs.live/huaxue/20190420/32311.html
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