本文選題：核苷酸氧化損傷修復(fù)酶MTH1 + 全新藥物設(shè)計��； 參考：《青島科技大學(xué)》2017年碩士論文

【摘要】：核苷酸氧化損傷修復(fù)酶MTH1通過作用于細(xì)胞核苷酸池,防止氧化損傷的嘌呤核苷酸錯誤的編入核酸分子中,從而間接維護遺傳物質(zhì)的穩(wěn)定性。研究顯示,腫瘤細(xì)胞的DNA氧化損傷修復(fù)機制存在很多缺陷,而MTH1酶則是維護腫瘤特別是RAS突變型腫瘤DNA分子正確復(fù)制及細(xì)胞增殖的關(guān)鍵。通過抑制MTH1酶的活性,腫瘤細(xì)胞內(nèi)氧化應(yīng)激水平會進一步上升,導(dǎo)致更多的DNA損傷從而引起腫瘤細(xì)胞增殖的停滯甚至凋亡,以達到腫瘤治療的目的。因此,核苷酸氧化損傷修復(fù)酶MTH1是RAS突變型腫瘤治療中小分子藥物的理想靶點。本文通過采用計算機輔助藥物設(shè)計方法,基于核苷酸氧化損傷修復(fù)酶MTH1的三維結(jié)構(gòu),及其相關(guān)抑制劑的分子結(jié)構(gòu)進行全新藥物設(shè)計。首先應(yīng)用碎片生長的方法,設(shè)計了683個化合物,接著對這些化合物進行ADME/Tox藥理學(xué)性質(zhì)評估及其分子對接的虛擬篩選,選擇出10種打分較高的化合物進行進一步的結(jié)合模式研究。對體系進行50ns的分子動力學(xué)平衡研究,通過考察其動力學(xué)穩(wěn)態(tài)并觀察其平衡后構(gòu)象進一步確定了4種結(jié)合最佳的分子。然后又基于骨架躍遷和藥效團篩選方法,構(gòu)建并篩選了537個全新分子結(jié)構(gòu),之后通過各虛擬篩選手段及其動力學(xué)模擬方法,最終選定2種最優(yōu)分子進行下一階段的研究。為了探索MTH1酶抑制劑的多靶標(biāo)作用,本文通過使用反向虛擬篩選的方法,對設(shè)計并篩選到的化合物進行反向藥效團搜索研究。從各分子靶向的前100個藥效團中篩選出靶向次數(shù)最多的大分子結(jié)構(gòu),通過進一步分析這些蛋白酶與相應(yīng)化合物的相互作用模式,研究這些蛋白質(zhì)分子的生物學(xué)作用,以考察這些小分子化合物的多靶標(biāo)特性及其可能的副作用。本文對化合物12即3-((((5-氨基吡唑并[1,5-c]嘧啶-3-基)甲基)氨基)甲基)苯酚進行了合成研究,通過逆合成路線分析,初步設(shè)計了一條簡便合成路線,并對中間體5-氨基吡唑并[1,5-c]嘧啶-3-甲醛的合成路線進行了進一步的優(yōu)化。本文通過使用計算機輔助藥物設(shè)計方法對核苷酸氧化損傷修復(fù)酶MTH1的抑制劑進行了全新設(shè)計,并進一步探索了相關(guān)化合物的合成,為MTH1相關(guān)抑制劑的研發(fā)奠定了基礎(chǔ)。
[Abstract]:Nucleotide oxidative damage repair enzyme (MTH1) indirectly maintains the stability of genetic material by acting on the cell nucleotide pool to prevent the oxidative damage of purine nucleotides from miscoding into nucleic acid molecules. Studies have shown that there are many defects in the repair mechanism of DNA oxidative damage in tumor cells, and MTH1 enzyme is the key to maintain the correct replication of DNA molecules and cell proliferation of tumor cells, especially RAS mutant tumors. By inhibiting the activity of MTH1 enzyme, the level of oxidative stress in tumor cells will rise further, leading to more DNA damage, thus leading to tumor cell proliferation arrest or even apoptosis, in order to achieve the purpose of tumor therapy. Therefore, nucleotide oxidative damage repair enzyme (MTH1) is an ideal target for small molecular drugs in the treatment of RAS mutant tumors. Based on the three-dimensional structure of nucleotide oxidative damage repair enzyme (MTH1) and the molecular structure of its related inhibitors, a new drug design was carried out by computer aided drug design (CAD). First, 683 compounds were designed by using the method of fragment growth. Then, the pharmacological properties of these compounds were evaluated by ADME/Tox and the virtual screening of molecular docking, and 10 compounds with higher scores were selected to further study the binding mode. The molecular dynamics equilibrium of 50ns system was studied. The four best binding molecules were further determined by investigating the kinetic stability and the conformation after observing the equilibrium. Then, 537 novel molecular structures were constructed and screened based on skeleton transition and pharmacophore screening methods. Then, two kinds of optimal molecules were selected for the next stage by virtual screening methods and kinetic simulation methods. In order to explore the multi-target effect of MTH1 enzyme inhibitors, reverse pharmacophore search was carried out on the designed and screened compounds by using reverse virtual screening method. The macromolecular structures with the largest number of targets were screened from the first 100 pharmacophore targeted by each molecule. The biological effects of these proteins were studied by further analyzing the interaction patterns of these proteases with the corresponding compounds. To investigate the multi-target properties of these small molecular compounds and their possible side effects. In this paper, the synthesis of compound 12 (3-Aminopyrazolido [1AZO5-c] pyrimidine-3-methyl-methyl) phenol was studied. A simple synthetic route was preliminarily designed through the analysis of the inverse synthesis route. The synthesis route of the intermediate 5-aminopyrazolyl [1 5-c] pyrimidine-3-formaldehyde was further optimized. In this paper, the inhibitors of nucleotide oxidative damage repair enzyme (MTH1) were designed by computer aided drug design (CAD), and the synthesis of related compounds was further explored, which laid a foundation for the research and development of MTH1 inhibitors.
【學(xué)位授予單位】：青島科技大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R914

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