本文選題：ATP競爭性抑制劑　切入點：變構(gòu)抑制劑　出處：《浙江大學》2014年博士論文　論文類型：學位論文

【摘要】：蛋白激酶B (PKB/Akt)作為良好的抗腫瘤藥物靶點,已有多種PKB抑制劑被廣泛研究并應用于腫瘤的治療。其中ATP競爭性抑制,變構(gòu)抑制劑,非ATP競爭性抑制劑和假底物抑制劑是當前研究最廣泛的PKB抑制劑。但是由于PKB亞型之間及PKB與其它激酶間的氨基酸序列存在高度同源性,因此PKB抑制劑的選擇性設計是PKB抑制劑研究領(lǐng)域的一個棘手的難題。 蛋白激酶選擇性抑制機理的研究可以為選擇性抑制劑的設計提供良好的基礎。而分子動力學模擬方法由于可以通過評價蛋白激酶-抑制劑復合物體系的穩(wěn)定性以及蛋白激酶與抑制劑之間的親和力來研究蛋白激酶選擇性抑制的機理,并在蛋白激酶選擇性抑制劑研究方面得到了廣泛的應用。 而二氫嘧啶酮類化合物和螺雜環(huán)取代的吲哚類化合物分別具有廣泛的生物活性與藥理活性,可以作為抗腫瘤藥,抗微生物藥等。因此通過Biginelli反應合成二氫嘧啶酮類化合物和螺雜環(huán)取代的吲哚類化合物引起了人們廣泛的研究興趣。 因此,本論文圍繞著PKB抑制劑設計合成、生物活性測試、分子模擬研究和Biginelli反應進行了以下研究： (1)、本文通過對PKA, PKBa, PKBa計算機模擬突變體和吡咯并嘧啶類抑制劑的9個復合物體系進行分子動力學模擬研究,在分析吡咯并嘧啶類抑制劑結(jié)合模式的基礎上,從模擬的角度合理地解釋了PKB抑制劑相對于PKA選擇性抑制PKB的機制,并成功地驗證了已報道的關(guān)于于PKB抑制劑相對于PKA選擇性的一些實驗研究結(jié)果。同時也提出了這類抑制劑的結(jié)構(gòu)修飾規(guī)律,指導這類抑制劑的設計。 (2)、本文通過對PKBa, ROCK1, PKBa計算機模擬突變體和吡啶類抑制劑的7個復合物體系進行分子動力學模擬研究,在分析吡啶類抑制劑結(jié)合模式的基礎上,從模擬的角度合理地解釋了PKB抑制劑相對于ROCK1選擇性抑制PKB的機制,成功地驗證了已報道的關(guān)于PKB抑制劑相對于ROCK1選擇性的一些實驗研究結(jié)果。同時也提出了這類抑制劑結(jié)構(gòu)修飾的規(guī)律,指導這類抑制劑的設計。 (3)、本文通過對PKBa與變構(gòu)抑制劑的3個復合物體系進行分子動力學模擬研究,從模擬的角度合理地解釋了變構(gòu)抑制劑的作用機制和結(jié)合模式,成功地驗證了已報道的關(guān)于PKB變構(gòu)抑制劑的實驗研究結(jié)果,并提出了這類抑制劑結(jié)構(gòu)修飾的規(guī)律,指導這類抑制劑的設計。 (4)、本文通過對PKB非ATP競爭性抑制劑進行3D-QSAR研究,同時對構(gòu)建的5個復合物體系進行分子動力學模擬研究,從模擬的角度合理地解釋了非ATP競爭性抑制劑的結(jié)合模式和PKB亞型選擇性機制,成功地驗證了已報道的關(guān)于非ATP競爭性抑制劑的實驗研究結(jié)果,同時根據(jù)非ATP競爭性抑制劑的3D-QSAR研究結(jié)果,提出了非ATP競爭性抑制劑結(jié)構(gòu)修飾的規(guī)律,指導這類抑制劑的設計。 (5)、本文通過PKBa與肽類假底物抑制劑的3個復合物體系進行分子動力學模擬研究,從模擬的角度合理地解釋了肽類假底物抑制劑的結(jié)合模式,成功地驗證了已報道的關(guān)于PKB假底物抑制劑的一些實驗研究結(jié)果。同時也提出了假底物抑制劑結(jié)構(gòu)修飾的規(guī)律,指導這類抑制劑的設計。 (6)、結(jié)合PKB分子模擬的結(jié)果及相關(guān)實驗結(jié)果,本文主要設計了9類化合物和合成了89個化合物,并對其中51個化合物進行了體外PKBa激酶的抑制實驗。其它化合物有待進行激酶抑制實驗。 (7)、本文研究了三氟甲磺酸镥崔花的和氯甲基二甲基氯硅烷(CMDMCS)參與的Biginelli反應。反應以醛/靛紅化合物/縮醛,1,3-二羰基化合物/縮酮,脲/硫脲為起始原料,反應高收率地得到了22個二氫嘧啶酮類化合物。其中,三氟甲磺酸镥可回收和重復使用,而氯甲基二甲基氯硅烷廉價易得,因而為該類化合物的制備提供了新的合成途徑,同時為該類化合物的進一步相關(guān)研究奠定了基礎。
[Abstract]:Protein kinase B (PKB/Akt) as anti-tumor drug targets is good, there are many kinds of PKB inhibitors are widely studied and applied in the treatment of cancer. The ATP competitive inhibitor, allosteric inhibitors, non competitive inhibitors of ATP and the false inhibitor is current research most widely used PKB inhibitors. But due to the amino acid sequence between PKB subtypes and PKB and other kinases exist between highly homologous, so the design of selective PKB inhibitors is a difficult problem in the research field of PKB inhibitors.
Study on protein kinase selective inhibition mechanism can provide a good foundation for the design of selective inhibitors. The molecular dynamics simulation method for stability evaluation mechanism can be through protein kinase inhibitor complex system and protein kinase inhibitors and inhibition of protein kinase selective affinity to study, and has been widely used in the study of protein kinase selective inhibitors.
Indole compounds and two hydrogen pyrimidinone compounds and spiro heterocyclic substituted respectively with biological activity and extensive pharmacological activity, can be used as antitumor drugs, anti microbial drugs. Therefore indole compounds synthesized through the Biginelli reaction of two hydrogen pyrimidinone compounds and substituted spiro heterocyclic compounds have attracted considerable research interests.
Therefore, this paper focuses on the design and synthesis of PKB inhibitors, biological activity test, molecular simulation research and Biginelli reaction.
(1), based on PKA, PKBa, 9 of the complex system simulation of mutant and pyrrolopyrimidine inhibitor PKBa by computer molecular dynamics simulation research, in the analysis of pyrrolopyrimidine inhibitor binding on the basis of the model, from the simulation can explain the mechanism of PKA PKB inhibitors with respect to the selective inhibition of PKB. And successfully verified reported about PKB inhibitors with respect to some experimental results on the selectivity of PKA. At the same time also proposed structure modification law of such inhibitors, guiding the design of such inhibitors.
(2), based on PKBa, ROCK1, 7 complex system simulation mutants and pyridine inhibitor PKBa by computer molecular dynamics simulation study, based on the analysis of pyridine inhibitor binding mode, from the simulation angle reasonably explained the mechanism of ROCK1 PKB inhibitors for the selective inhibition of PKB, successfully verified it has been reported about PKB inhibitors with respect to some experimental results on the selectivity of ROCK1. At the same time put forward the modified inhibitors of this kind of guiding the design of inhibitors.
(3), the molecular dynamics simulation research through 3 complexes of PKBa and allosteric inhibitors, from the simulation angle reasonably explained the mechanism of allosteric inhibitors and binding mode, successfully verified about the PKB allosteric inhibitor of the experiment research results, and put forward the modification of these inhibitors the structure of law, guiding the design of such inhibitors.
(4), based on the study of 3D-QSAR PKB non competitive inhibitors of ATP, while the 5 complex system of molecular dynamics simulation, from the simulation can explain the non competitive inhibitors of ATP binding mode and PKB subtype selective mechanism to verify the experimental results about non competitive inhibitors of ATP have been reported, according to the results of 3D-QSAR study on non competitive inhibitors of ATP, proposed the modified non ATP competitive inhibitors of this kind of guiding the design of inhibitors.
(5), this paper studied by molecular dynamics simulations of 3 complexes with PKBa peptide pseudosubstrate inhibitor, from the simulation angle can reasonably explain the binding mode of peptide pseudosubstrate inhibitor, has been successfully verified reports about PKB inhibitors pseudosubstrate some experimental results. At the same time also proposed modified materials inhibitor of the design direction of this inhibitor.
(6) combined with the results of PKB molecular simulation and related experimental results, 9 compounds and 89 compounds were synthesized, and 51 compounds were tested for inhibition of PKBa kinase in vitro. Other compounds need to undergo kinase inhibition test.
(7), this paper studies three trifluoroacetic acid and methyl chloride lutetium Cui flower two (CMDMCS) Biginelli in the reaction of methyl chlorosilane. Reaction with aldehydes / isatin compounds / acetal, ketal / 1,3- two carbonyl compounds, urea / thiourea as the starting materials, the reaction obtained in high yield 22 two hydrogen pyrimidine ketone compounds. Among them, three trifluoroacetic acid lutetium Recyclable and reused, and chloromethyl two methyl chlorosilane is cheap and thus for the preparation of the compound provides a new synthetic route, and lays a foundation for further research of the compounds.

【學位授予單位】：浙江大學
【學位級別】：博士
【學位授予年份】：2014
【分類號】：R914

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本文編號：1569103