本文選題：氨基肽酶N + APN/CD13抑制劑��； 參考：《南昌大學(xué)》2017年碩士論文

【摘要】：氨基肽酶N(APN)/CD13是一種多功能蛋白酶,存在于人體組織和細(xì)胞當(dāng)中,具有多種多樣的功能,與腫瘤的發(fā)生,免疫系統(tǒng),疼痛等緊密相關(guān)。APN/CD13還可作為多種人類病毒的受體,如冠狀病毒,以及參與抗原的修飾和抗原呈遞等過程。實(shí)驗(yàn)表明在炎癥性疾病和癌癥(實(shí)體和血液腫瘤)中APN/CD13均過度表達(dá),且研究已經(jīng)證實(shí)APN/CD13參與了腫瘤發(fā)展的多個(gè)生理過程,如腫瘤血管的生成,侵襲以及腫瘤轉(zhuǎn)移等,因此APN/CD13已經(jīng)成為了研究新型抗腫瘤藥物的重要方向。本課題依據(jù)APN/CD13的三維結(jié)構(gòu)特點(diǎn)進(jìn)行設(shè)計(jì),引入類肽的設(shè)計(jì)理念,鏈接基團(tuán)引入了丙氨酸和亮氨酸,在充分考慮本實(shí)驗(yàn)室活性研究結(jié)果的基礎(chǔ)上,連接具有抗腫瘤活性的2-氨基-1,3,4-噻二唑結(jié)構(gòu)以及活性中間體R-扁桃酸,結(jié)合計(jì)算機(jī)虛擬對接模擬技術(shù),對結(jié)構(gòu)進(jìn)行優(yōu)化,最終合成了具有抗APN/CD13活性的兩個(gè)系列的二十三個(gè)新的化合物。對化合物進(jìn)行初步的體外抑酶活性試驗(yàn),篩選出9m和10j兩個(gè)抑酶效果較好的化合物,其中9m為丙氨酸系列的化合物,10j為亮氨酸系列的化合物。從結(jié)果中我們可以發(fā)現(xiàn)當(dāng)芳環(huán)被甲氧基取代時(shí),抑酶作用最強(qiáng),其次為硝基等其它的吸電子取代基,而供電子基團(tuán)為取代基時(shí),抑酶活性最低。利用計(jì)算機(jī)技術(shù)進(jìn)行分子對接,得到的結(jié)果顯示兩個(gè)化合物均能夠與氨肽酶N的催化鋅離子發(fā)生螯合,而且化合物當(dāng)中的多種原子可以與酶形成多個(gè)氫鍵,并與APN/CD13的疏水口袋的相互作用,加強(qiáng)了化合物與APN/CD13的相互作用。篩選出的兩個(gè)活性較優(yōu)的化合物可以作為先導(dǎo)化合物繼續(xù)進(jìn)一步的研究,該實(shí)驗(yàn)結(jié)果也可以作為依據(jù)用于繼續(xù)改進(jìn)優(yōu)化化合物的基團(tuán)和骨架,以便合成活性更好的化合物。
[Abstract]:Aminopeptidase N(APN)/CD13 is a multifunctional protease that exists in human tissues and cells. It has a variety of functions and is closely related to tumorigenesis, immune system, pain and so on. APN / CD13 can also be used as a receptor for many human viruses. Such as coronavirus, and participate in antigen modification and antigen presentation and other processes. The results show that APN/CD13 is overexpressed in inflammatory diseases and cancer (solid and blood tumors), and it has been proved that APN/CD13 is involved in many physiological processes of tumor development, such as angiogenesis, invasion and metastasis of tumor. Therefore, APN/CD13 has become an important direction in the study of new anti-tumor drugs. According to the three-dimensional structure characteristics of APN/CD13, this paper introduces the design idea of peptide like peptide, and the linked group introduces alanine and leucine, on the basis of fully considering the results of our laboratory activity research. The structure of 2-amino-1-tiadiazole with anti-tumor activity and the active intermediate R-mandelic acid were connected. The structure was optimized by computer virtual docking simulation technique. Finally, 23 new compounds of two series with anti-APN/CD13 activity were synthesized. The enzyme inhibition activity of the compounds in vitro was preliminarily tested. Two compounds, 9m and 10j, were screened out, among which 9m was alanine series and 10j was leucine. From the results we can find that when the aromatic ring is replaced by methoxy the inhibitory activity is the strongest followed by other electron-absorbing substituents such as nitro and so on while the inhibitory activity is the lowest when the donor group is the substituent. The results of molecular docking show that both compounds can chelate with zinc ion catalyzed by aminopeptidase N, and many atoms in the compounds can form multiple hydrogen bonds with the enzyme. The interaction with APN/CD13 hydrophobic pocket strengthens the interaction between compound and APN/CD13. The two compounds with better activity can be further studied as lead compounds. The results can also be used as the basis for further improvement of the groups and skeletons of the compounds in order to synthesize compounds with better activity.
【學(xué)位授予單位】：南昌大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R914

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本文編號(hào)：1799446