吡啶类化合物解毒神经毒剂的机理研究及理论设计

发布时间：2018-04-23 15:50

本文选题：有机磷化合物 + 乙酰胆碱酯酶　；参考：《哈尔滨工业大学》2016年硕士论文

【摘要】：有机磷(Organophosphorus,OP)化合物主要通过抑制乙酰胆碱酯酶(acetylcholinesterase,AChE)的活性造成神经系统功能紊乱,产生中毒现象。目前临床上用于治疗有机磷中毒的主要方法是通过肟类(oxime)化合物来重活化磷酰化的有机磷-乙酰胆碱酯酶(OP-AChE)加合物,从而恢复乙酰胆碱酯酶的活性。但是,在重活化反应的同时,磷酰化的OP-AChE加合物还会发生一个竞争性的不可逆转的去烷基化反应,称为“老化”反应,这导致了AChE的永久性失活。最近,Topczewski课题组设计并合成了一系列可用作甲基化试剂的N-甲基-2-甲氧基吡啶化合物,它能够甲基化老化的OP-AChE加合物的最小模型,为实现老化反应的可逆提供了参考。然而,目前还没有类似的N-甲基-2-甲氧基吡啶化合物能够甲基化真实老化OP-AChE加合物的报道。基于此,本课题探究了N-甲基-2-甲氧基吡啶类化合物能甲基化老化的OP-ACh E加合物的最小模型(甲基甲烷磷酸单阴离子)的反应机理,并预测了其甲基化真实老化的OP-AChE加合物的反应能垒,通过比较两个反应在结构以及机理方面的差异,阐明了影响甲基化反应活化能的关键因素,为设计活性的更高甲基化试剂提供理论指导。通过密度泛函理论(DFT)计算方法和量子力学/分子力学(QM/MM)结合计算方法,本文选了9种取代基不同的N-甲基-2-甲氧基吡啶类化合物(编号分别为1-9),揭示了N-甲基-2-甲氧基吡啶分别甲基化甲基甲烷磷酸单阴离子、老化的Sarin-AChE化合物反应的机理。结果表明:小分子模型反应是一个典型的SN2反应,而不是一个多步进攻反应,计算的自由能和实验值非常接近;而N-甲基-2-甲氧基吡啶甲基化老化的Sarin-AChE加合物反应也是一个SN2反应,但是其反应能垒要显著高于小分子模型反应,以活性最高的化合物2(N-甲基-2-甲氧基-3-F-吡啶)为例,能垒值为30.4±3.5 kca/mol(算术平均自由能)或者26.6 kcal/mol(玻尔兹曼平均自由能),显示这个反应很难发生。通过结构和机理分析,我们发现化合物2和AChE的W86残基形成了一个π-π堆积作用,而这个作用使得化合物2本身不能像小分子模型反应那样接近Sarin来发动甲基化反应,导致能垒升高。最后,根据计算结果,本文提出了几种改进吡啶类化合物甲基化反应活性的策略,为实现老化的Sarin-AChE加合物的逆转提供了理论指导。
[Abstract]:Organophosphorus organophosphorus (OPP) compounds cause nervous system dysfunction by inhibiting the activity of acetylcholinesterase acetylcholinesterase (acetylcholinesterase). At present, the main method for the treatment of organophosphorus poisoning is to reactivate the organophosphorus-acetylcholinesterase (OP-AChE) adducts through oxime compounds to restore the activity of acetylcholinesterase. However, at the same time of reactivation, the phosphorylated OP-AChE adducts will undergo a competitive and irreversible dealkylation reaction, called "aging" reaction, which leads to the permanent inactivation of AChE. Recently, Topczewski team designed and synthesized a series of N-methyl-2-methoxy pyridine compounds which can be used as methylating reagents. It can be used as the minimum model of OP-AChE adducts for methylation aging, which provides a reference for realizing the reversible aging reaction. However, there are no reports that N-methyl-2-methoxy pyridine compounds can methylate real aging OP-AChE adducts. Based on this, the reaction mechanism of N-methyl-2-methoxy pyridine compounds with methylated aging OP-ACh E adducts (methyl methane phosphate monoanion) was investigated. The reaction energy barrier of the methylated OP-AChE adducts was predicted. The key factors affecting the activation energy of the methylation reactions were discussed by comparing the differences in structure and mechanism between the two reactions. It provides theoretical guidance for the design of higher methylation reagents with high activity. By using density functional theory (DFT) and quantum / molecular mechanics (QM / MMM) method, Nine N-methyl-2-methoxy pyridine compounds with different substituents (numbered 1-9) were selected in this paper. The reaction mechanism of N-methyl-2-methoxy pyridine methylated methyl methane phosphate monoanion and aging Sarin-AChE compound was revealed. The results show that the small molecular model reaction is a typical SN2 reaction, not a multi-step attack reaction, and the calculated free energy is very close to the experimental value. The Sarin-AChE adduct of N-methyl-2-methoxypyridine methylation is also a SN2 reaction, but its energy barrier is significantly higher than that of the small-molecule model reaction. For example, the most active compound 2N- methyl-2-methoxy-3-F- pyridine is used as an example. The energy barrier of 30.4 卤3.5 KCA / mol (arithmetic mean free energy) or 26.6 kcal / mol (Boltzmann mean free energy) shows that this reaction is difficult to occur. Based on the structure and mechanism analysis, we found that compound 2 and the W86 residue of AChE formed a 蟺-蟺 stacking effect, which made compound 2 itself not close to Sarin to initiate methylation as the small molecular model reaction. Cause the energy barrier to rise. Finally, based on the calculated results, several strategies to improve the methylation activity of pyridine compounds are proposed, which provide theoretical guidance for the reversal of aging Sarin-AChE adducts.
【学位授予单位】：哈尔滨工业大学
【学位级别】：硕士
【学位授予年份】：2016
【分类号】：O643.12

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