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基于受體—配體空間構(gòu)象信息設(shè)計(jì)IL-6拮抗多肽

發(fā)布時(shí)間:2019-06-07 14:49
【摘要】:自從1997年William等通過(guò)X射線晶體衍射分析確定了人IL-6的三維結(jié)構(gòu)以來(lái),人們?cè)谌薎L-6及其受體拮抗劑的研究方面已經(jīng)取得了一定成果,但因其特異性差,且不能安全、長(zhǎng)期、有效地抑制體內(nèi)IL-6的活性,所以限制了它們?cè)谂R床上的應(yīng)用。本研究擬根據(jù)IL-6/sIL-6R/gp130相互作用復(fù)合物的三維結(jié)構(gòu),通過(guò)距離幾何學(xué)、分子間氫鍵形成理論探討IL-6與其受體(IL-6R、gp130)的作用模式,借助虛擬篩選與計(jì)算機(jī)輔助合理設(shè)計(jì)相結(jié)合的方法,合理篩選獲得IL-6小分子拮抗肽,初步建立基于受體—配體相互作用空間構(gòu)象設(shè)計(jì)配體拮抗劑的可行性方案。同時(shí),針對(duì)設(shè)計(jì)的IL-6小分子拮抗肽,從實(shí)驗(yàn)上對(duì)合成短肽的體外生物學(xué)活性進(jìn)行了評(píng)價(jià),希望為臨床治療IL-6相關(guān)疾病提供更有效的先導(dǎo)化合物。研究?jī)?nèi)容具體如下: 一.IL-6小分子拮抗肽的設(shè)計(jì) 根據(jù)IL-6/sIL-6R/gp130相互作用復(fù)合物的三維結(jié)構(gòu),通過(guò)計(jì)算機(jī)圖形學(xué)技術(shù)、距離幾何學(xué)、分子間氫鍵作用確定hIL-6/hIL-6R/gp130相互作用的功能域,理論分析影響配基—受體作用的功能域結(jié)構(gòu)信息及其作用模式。利用位點(diǎn)連接法計(jì)算機(jī)輔助設(shè)計(jì)hIL-6拮抗肽,從頭搭建拮抗肽空間構(gòu)象,經(jīng)分子力學(xué)、動(dòng)力學(xué)優(yōu)化獲得的拮抗肽穩(wěn)定構(gòu)象與受體IL-6R進(jìn)行分子對(duì)接,從理論上構(gòu)建拮抗肽/hIL-6R相互作用復(fù)合物空間結(jié)構(gòu)并對(duì)IL-6拮抗肽進(jìn)行生物學(xué)功能評(píng)價(jià)。 二、IL-6小分子拮抗肽生物學(xué)功能評(píng)價(jià) ①通過(guò)MTT法、~3H—TdR摻入法初步驗(yàn)證IL-6小分子拮抗肽的活性。選擇IL-6依賴(lài)型細(xì)胞系—人多發(fā)性骨髓瘤細(xì)胞XG-7通過(guò)細(xì)胞學(xué)方法檢測(cè)拮抗肽對(duì)其增殖的影響,進(jìn)而評(píng)價(jià)其對(duì)IL-6活性的影響。結(jié)果表明,設(shè)計(jì)的IL-6小分子拮
[Abstract]:Since William et al determined the three-dimensional structure of human IL-6 by X-ray crystal diffraction analysis in 1997, some achievements have been made in the study of human IL-6 and its receptor antagonists, but it is not safe because of its poor specificity. Long-term, effectively inhibit the activity of IL-6 in vivo, so their clinical application is limited. In this study, according to the three-dimensional structure of IL-6/sIL-6R/gp130 interaction complex, the interaction mode between IL-6 and its receptor (IL-6R,gp130) was discussed by distance geometry and intermolecular hydrogen bond formation theory. By means of virtual screening and computer aided reasonable design, IL-6 small molecule antagonistic peptides were reasonably screened, and a feasible scheme for designing ligand antagonists based on receptor-ligand interaction space conformational design was established. At the same time, the biological activity of the synthesized short peptide was evaluated in vitro for the designed IL-6 small molecule antagonistic peptide, in the hope of providing more effective lead compounds for the clinical treatment of IL-6 related diseases. The research contents are as follows: 1. The design of IL-6 small molecule antagonistic peptides is based on the three-dimensional structure of IL-6/sIL-6R/gp130 interaction complex. The functional domain of hIL-6/hIL-6R/gp130 interaction was determined by computer graphics, distance geometry and intermolecular hydrogen bond interaction. The functional domain structure information and its action mode affecting ligand-receptor interaction were analyzed theoretically. HIL-6 antagonistic peptides were designed by computer aided design with site connection method. The spatial conformations of antagonistic peptides were constructed from scratch. The stable conformations of antagonistic peptides optimized by molecular mechanics and kinetics were linked to the receptor IL-6R. The spatial structure of antagonistic peptide / hIL-6R interaction complex was constructed theoretically and the biological function of IL-6 antagonistic peptide was evaluated. 2. Evaluation of biological function of IL-6 small molecule antagonistic peptide 1 the activity of IL-6 small molecule antagonistic peptide was preliminarily verified by MTT method and ~ 3H-TdR incorporation method. Human multiple myeloma cell line XG-7, a IL-6 dependent cell line, was selected to detect the effect of antagonistic peptides on its proliferation by Cytology, and then to evaluate the effect of antagonistic peptides on IL-6 activity. The results show that the designed IL-6 small molecules are antagonistic.
【學(xué)位授予單位】:中國(guó)人民解放軍軍事醫(yī)學(xué)科學(xué)院
【學(xué)位級(jí)別】:碩士
【學(xué)位授予年份】:2005
【分類(lèi)號(hào)】:R392

【參考文獻(xiàn)】

相關(guān)期刊論文 前3條

1 康曉平,任蘊(yùn)芳,沈倍奮;人IL-6及其受體拮抗劑的研究進(jìn)展[J];國(guó)外醫(yī)學(xué)(分子生物學(xué)分冊(cè));2001年04期

2 宋倫;多發(fā)性骨髓瘤的生長(zhǎng)調(diào)控機(jī)制[J];微生物學(xué)免疫學(xué)進(jìn)展;2001年04期

3 宋倫,沈倍奮;白細(xì)胞介素6在人骨髓瘤細(xì)胞系XG-7中的信號(hào)轉(zhuǎn)導(dǎo)途徑與生物學(xué)效應(yīng)[J];中華醫(yī)學(xué)雜志;2000年11期



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