本文選題：視神經(jīng)脊髓炎譜系疾病　切入點(diǎn)：認(rèn)知障礙　出處：《揚(yáng)州大學(xué)》2017年碩士論文

【摘要】：目的:視神經(jīng)脊髓炎譜系疾病(neuromyelitis optica spectrum disorders,NMOSD),是一種中樞神經(jīng)系統(tǒng)炎性脫髓鞘性自身免疫性疾病。不及時(shí)治療,可能會(huì)導(dǎo)致失明,四肢癱瘓甚至死亡。NMOSD主要侵犯目標(biāo)是視神經(jīng)和脊髓,但其是否對(duì)患者的認(rèn)知功能造成影響,目前尚未有定論。視神經(jīng)脊髓炎譜系疾病的經(jīng)典發(fā)病機(jī)制為水通道蛋白4(Aquaporin 4,AQP4)抗原抗體反應(yīng),然而臨床上尚未有直接針對(duì)AQP4靶標(biāo)的抑制劑類藥物。我們用數(shù)理統(tǒng)計(jì)的方法分析了視神經(jīng)脊髓炎(neuromyelitis optica,NMO)對(duì)認(rèn)知的影響,并且以AQP4為靶標(biāo),使用分子探針分析活性中心;使用分子動(dòng)力學(xué)方法,基于對(duì)關(guān)鍵氨基酸的分析,探究了 AQP4的口袋特征;并采取多種方法篩選設(shè)計(jì)新藥的先導(dǎo)化合物,為針對(duì)影響視神經(jīng)脊髓炎譜系疾病的新藥發(fā)現(xiàn)做出有益的探索。材料與方法:我們基于已有的文獻(xiàn)報(bào)道,采用神經(jīng)心理測(cè)試的方法,去除受教育程度、年齡、性別等影響因素,對(duì)24歲到60歲之間的227名NMO患者和185健康受試者以及129名多發(fā)性硬化癥(multiple sclerosis,MS)患者進(jìn)行認(rèn)知功能的評(píng)估分析。在國家超算平臺(tái)上,使用分子動(dòng)力學(xué)計(jì)算的方法,模擬AQP4蛋白的生理狀態(tài),構(gòu)建了 POPC雙分子層和OAPs四聚體結(jié)構(gòu),并進(jìn)行了關(guān)鍵氨基酸突變體的動(dòng)態(tài)分析。分析優(yōu)化了 RCSB上目前已有的AQP4晶體結(jié)構(gòu)數(shù)據(jù),研究了活性中心的關(guān)鍵區(qū)域。對(duì)ZINC、DrugBank和小分子肽組合庫等數(shù)據(jù)庫進(jìn)行了基于受體的計(jì)算機(jī)輔助藥物篩選。結(jié)果:我們研究結(jié)果表明,NMO患者的語言學(xué)習(xí)能力、執(zhí)行能力、聽覺/視覺加工能力和記憶能力等認(rèn)知功能與健康人群相比,都有所下降。分子動(dòng)力學(xué)計(jì)算結(jié)果顯示對(duì)AQP4蛋白上與視神經(jīng)脊髓炎譜系疾病經(jīng)典自身免疫反應(yīng)相關(guān)的關(guān)鍵氨基酸進(jìn)行組氨酸突變,會(huì)跨越細(xì)胞外環(huán)通過多米諾效應(yīng)引起細(xì)胞外環(huán)A的空間構(gòu)象改變。這有可能是導(dǎo)致AQP4基因多態(tài)性影響視神經(jīng)脊髓炎易患性的機(jī)制之一。分子探針探測(cè)到AQP4蛋白上唯一一個(gè)適合與NMOSD-IgG反應(yīng)的漏斗狀的活性中心,分子動(dòng)力學(xué)結(jié)果提示該活性中心的核心區(qū)域位于LoopA下方。通過分析篩選結(jié)果中評(píng)分靠前的3000個(gè)化合物,發(fā)現(xiàn)了以雙甾體類綴合物和稠雜環(huán)化合物綴合物為代表的多個(gè)先導(dǎo)化合物。結(jié)論:NMO患者的認(rèn)知功能會(huì)有所損傷,AQP4抗原抗體反應(yīng)目前是視神經(jīng)脊髓炎譜系疾病重要的診斷標(biāo)準(zhǔn),但它更是關(guān)鍵的治療靶標(biāo)。基于受體晶體結(jié)構(gòu)的計(jì)算化學(xué)分析顯示AQP4具備良好的藥物靶標(biāo)特征。以此為靶標(biāo)篩選獲得的先導(dǎo)化合物,可以應(yīng)用于基礎(chǔ)研究,提高我們對(duì)視神經(jīng)脊髓炎譜系疾病相關(guān)發(fā)病機(jī)制的認(rèn)識(shí);也可以應(yīng)用于后續(xù)的通過化合物結(jié)構(gòu)優(yōu)化和系統(tǒng)的臨床前試驗(yàn)而獲得候選藥物。另外,這些先導(dǎo)物并非僅僅適用于視神經(jīng)脊髓炎譜系疾病的研究,也適用于其他一些與水通道蛋白具有相關(guān)性的疾病的研究。
[Abstract]:Objective: neuromyelitis optica spectrum disordersNMOSD is an inflammatory demyelinating autoimmune disease of the central nervous system. If not treated in time, it may lead to blindness, quadriplegia or even death. The main targets of NMOSD are optic nerve and spinal cord. However, it has not been concluded whether it will affect the cognitive function of the patients. The classic pathogenesis of optic neuromyelitis is the antigen-antibody response of aquaporin 4(Aquaporin 4 (AQP4). However, there are no direct inhibitors for AQP4 targets in clinic. We analyzed the effects of neuromyelitis neuromyelitis on cognition by means of mathematical statistics, and used AQP4 as the target, using molecular probes to analyze the active centers. Based on the analysis of key amino acids, the pocket characteristics of AQP4 were explored using molecular dynamics, and various methods were used to screen the leading compounds for the design of new drugs. Materials and methods: based on the existing literature, we used neuropsychological tests to remove the influence factors such as education level, age, sex and so on. The cognitive function of 227 NMO patients aged 24 to 60 and 185 healthy subjects and 129 multiple sclerosis patients with multiple sclerosis were evaluated and analyzed. The structure of POPC bilayer and OAPs tetramer was constructed by simulating the physiological state of AQP4 protein, and the key amino acid mutants were dynamically analyzed. The existing AQP4 crystal structure data on RCSB were analyzed and optimized. The key regions of active centers were studied. The receptor-based computer aided drug screening was carried out on databases such as ZINCX DrugBank and small molecular peptide combination libraries. Results: our results showed that NMO patients had language learning ability and executive ability. Cognitive functions such as auditory / visual processing and memory were compared to those of healthy people. The molecular dynamics analysis showed that the key amino acids related to the classical autoimmune reaction in the AQP4 protein were mutated by histidine. It may be one of the mechanisms leading to the polymorphism of AQP4 gene affecting the susceptibility of optic neuromyelitis. The molecular probe detects the AQP4 protein. The only funnel-like active center suitable for reaction with NMOSD-IgG, Molecular dynamics results suggest that the core region of the active center lies below LoopA. Several leading compounds, represented by disteroidal conjugates and fused heterocyclic conjugates, were found. Conclusion the cognitive function of the patients with NMO may be impaired and the antigen-antibody reaction of AQP4 may be an important diagnostic criterion for optic neuromyelitis lineage diseases at present. But it is a key therapeutic target. Computational chemical analysis based on the crystal structure of the receptor shows that AQP4 has good drug targeting characteristics. To raise our awareness of the pathogenesis associated with optic neuromyelitis, and to apply it to subsequent drug candidates through compound structure optimization and systematic preclinical trials. These precursors are not only suitable for the study of optic neuromyelitis spectrum diseases, but also for other diseases related to aquaporins.
【學(xué)位授予單位】：揚(yáng)州大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R744.52
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本文編號(hào)：1657720