基于密度泛函理论和QSAR方法研究有机物降解机制、急性毒性及致癌性

发布时间：2018-05-10 09:41

  本文选题：QSAR + 急性毒性　； 参考：《山东大学》2016年博士论文

【摘要】：随着化学工业的发展,越来越多新型化学品进入了人类的生活。根据美国化学文摘(Chemical Abstracts Service, CAS)的最新统计数据,目前注册的已发现和合成的化学物质总数已超过1亿种,而其中很多物质对环境和人类健康是有害的。面对数目如此庞大的化学物质,获得其毒性信息从而进行合理的监管和使用,是保护人类和环境免受危害的根本方法。然而根据统计,目前处于监管状态下的化学品仅有30多万种,绝大多数化学品缺少毒性信息,存在着巨大的数据缺口。而传统生物实验方法耗时长、花费大,无法满足大量化学品急需测试的需要,且与目前提倡的动物保护“3R(替代(Replacement)、减少(Reduction)和优化(Refinement))原则”相悖,因此能快速高效地获取化学品生物毒性数据的计算机模拟预测方法一定量构效关系(Quantitative structure-activity relationship, QSAR)方法已被越来越多的研究者所接受和使用。丰富的实验数据是进行QSAR研究的基础,只有在数据充足的前提下才能够借助计算机、应用统计学方法构建出合理的构效关系方程,然后结合生物化学及物理化学等相关知识,总结出化合物性质变化和分子结构特征变化之间的联系及规律,进而通过已知的分子结构特征对化合物的未知性质进行预测。因此,QSAR的研究对象应该是具有丰富实验数据的性质变量。目前在环境及生态毒理学领域常见的性质变量有急性毒性、慢性毒性、致癌性和皮肤敏感性等。本论文选择其中的急性毒性和致癌性进行了QSAR研究。QSAR研究成功的一个重要因素是获取合理准确的分子结构及相应的结构特征变量,为此需要对分子结构进行合理的几何优化。本论文中的分子结构优化都是在密度泛函理论(Density Functional Theory, DFT)方法的MPWB1K/6-31+G(d,p)水平下进行的,并且通过研究OH自由基引发的灭多威在大气中的降解机制对该水平的优化方法进行了实际效用的验证,在此基础上开展了有机物对啮齿动物致癌性和有机物对水生生物急性毒性的研究。本论文的主要研究内容及成果总结如下：(1)基于DFT方法研究OH自由基引发的灭多威在大气中降解机理灭多威是一种氨基甲酸酯类农药,主要用作广谱杀虫剂,但其对动物和人类也会产生毒害,因此研究其在大气中的降解机制具有重要的实际意义。本文研究了灭多威两种同分异构体在大气中O2、NO和H20存在的情况下由OH自由基引发的降解反应。在DFT方法的MPWB1K/6-31+G(d,p)水平下对反应物、中间体和产物进行了几何结构优化和频率计算,构建了反应的势能剖面图并讨论了所有可能的降解路径。采用小曲率隧道效应(small-curvature tunneling,SCT)校正的正则变分过渡态理论(Canonical variational theory, CVT)计算了每条反应路径在200-400K温度范围内基元反应的速率常数。研究发现,灭多威两种同分异构体的反应状况非常相似,既可以反生OH自由基加成反应,也可以发生H原子抽提反应。根据反应速率常数的分支比可以看出,对于Z式异构体,常温下抽提反应占较大比重,随着温度上升,加成反应比重上升。而对于E式异构体,常温下加成反应占较大比重,并随着温度上升比重不断增大。除此之外,还计算了两种同分异构体的大气寿命,目前还未见其他有关报道。(2)基于DFT方法研究有机物对啮齿动物致癌性的QSAR预测模型本论文基于CPDB肿瘤实验数据库,选择数据最多的肝脏肿瘤实验数据作为分析研究对象。通过对比雌雄两种性别啮齿生物的肿瘤实验数据,发现多种化合物存在明显差异,而且总体而言,雌性实验动物对致癌物表现出比雄性更强的耐受性。因此,综合考虑分子的结构特征,构建了有环化合物对雄性大鼠、无环化合物对雄性大鼠、有环化合物对雌性大鼠、无环化合物对雌性大鼠、有环化合物对雄性小鼠、无环化合物对雄性小鼠、有环化合物对雌性小鼠、无环化合物对雌性小鼠等八个定量预测模型。然后根据模型、结合已有知识对致癌机理进行了讨论。研究所构建的预测模型可以为研究性别对致癌作用的影响以及危险物质的管理提供重要的理论支持。(3)基于DFT方法研究有机物对水生生物急性毒性QSAR预测模型本章选择有机物对不同营养级典型水生生物(包括鱼类和水蚤)的急性毒性作为研究对象,基于DFT方法优化的分子结构分别构建了QSAR预测模型并进行了对比分析。在鱼类的急性毒性实验中,黑头呆鱼是最常用的实验对象之一,因此具有丰富的实验数据,为利用QSAR方法研究有机物的急性毒性预测模型提供了重要的数据支撑。本论文搜集整理了963种有机物对黑头呆鱼的96小时急性毒性实验数据,在DFT方法的MPWB1K/6-31+G(d,p)水平上对所有化合物的分子进行了几何结构优化,选择Dragon描述符和辛醇水分配系数logKow作为建模的备选变量,借助遗传算法和多元线性回归构建了目前数据集最大的黑头呆鱼急性毒性预测通用模型。除此之外,根据毒性比率及有机物毒性作用方式的划分,分别构建了麻醉性毒物和过量毒性毒物的急性毒性局域预测模型。大型蚤属于世界种,是毒性实验标准测试生物,具有丰富的实验数据。本章搜集整理了479种有机物对大型蚤的48小时急性毒性实验数据,同样在DFT方法的MPWB1K/6-31+G(d,p)水平上进行了化合物的几何结构优化,选择Dragon描述符及logKow作为建模的备选变量,借助遗传算法和多元线性回归构建了通用的急性毒性预测模型。除此之外，参考Verhaar区分框架,利用毒性比率将所研究化合物进行了毒性作用机制的分类并分别构建了QSAR模型,借助模型讨论了每种机制化合物的作用机理。最后,将有机物对黑头呆鱼和大型蚤呈现出的不同毒性作用机制进行了对比。研究发现,大型蚤对毒物的敏感性要高于黑头呆鱼；除了苯胺类物质,硫代磷酸酯类物质对黑头呆鱼和大型蚤的毒性也存在明显差异,其对黑头呆鱼仅表现为麻醉毒性,对大型蚤却呈现出过量毒性。
[Abstract]:With the development of the chemical industry, more and more new chemicals have entered human life. According to the latest statistics of Chemical Abstracts Service (CAS), more than 100 million kinds of chemicals have been found and synthesized, and many of them are harmful to the environment and human health. It is a fundamental way to protect human and environment from harm by obtaining such huge chemicals and obtaining its toxic information, which is the fundamental way to protect human and environment from harm. However, according to statistics, there are only about 300000 kinds of chemicals under supervision. Most chemicals are lacking in toxic information and there are huge data gaps. Biological experiments are time-consuming and costly to meet the needs of a large number of chemicals needed to test, and are contrary to the proposed animal protection "3R (Replacement), Reduction and Refinement"), so a computer simulation prediction method for obtaining chemical biological toxicity data quickly and efficiently The Quantitative structure-activity relationship (QSAR) method has been accepted and used by more and more researchers. The rich experimental data is the basis of QSAR research. Only with the sufficient data, a reasonable structure effect relation equation can be constructed with the help of the computer. The related knowledge of Biochemistry and physicochemistry, summarizes the relation and law between the properties of compounds and the changes of molecular structure characteristics, and then predicts the unknown properties of the compounds by the known molecular structure characteristics. Therefore, the research object of QSAR should be the property variable with rich and rich experimental data. The common variables in the field of ecotoxicology are acute toxicity, chronic toxicity, carcinogenicity, and skin sensitivity. In this paper, the acute toxicity and carcinogenicity of the QSAR are chosen. An important factor in the success of.QSAR research is to obtain a reasonable and accurate molecular structure and structural characteristic variables. The structure optimization is reasonable. The optimization of molecular structure in this paper is carried out under the MPWB1K/6-31+G (D, P) level of the Density Functional Theory (DFT) method, and the actual utility of the optimization method of the degradation of the Do-win in the atmosphere is studied by studying the degradation machine of the OH free radical. On this basis, the study on the carcinogenicity of organic substances to rodents and the acute toxicity of organic substances to aquatic organisms is carried out. The main contents and results of this paper are summarized as follows: (1) the study of the mechanism of the degradation of Do-win induced by OH radical based on the degradation mechanism of Do-win in the atmosphere is a kind of carbamate pesticide, which is mainly used as a wide range. Insecticides, however, are also toxic to animals and humans, so it is of great practical significance to study their degradation mechanism in the atmosphere. In this paper, the degradation reaction caused by two isomers in the atmosphere under the presence of O2, NO and H20 in the atmosphere was investigated by the OH free radical. The reaction at the MPWB1K/6-31+G (D, P) level of the DFT method was in response to the reaction. The materials, intermediates and products were optimized for geometric structure and frequency calculation. The potential energy profile of the reaction was constructed and all possible degradation paths were discussed. The regular variational transition state theory (Canonical variational theory, CVT) corrected by the small-curvature tunneling (SCT) was used to calculate each reaction path in 20 The rate constant of the base element reaction in the temperature range of 0-400K has been found. It is found that the reaction condition of two isomers of the Do-win is very similar, which can both reverse the OH radical addition reaction and the H atom extraction reaction. According to the branch ratio of the reaction rate constant, the extraction reaction of the Z isomer at normal temperature is a large proportion. As the temperature rises, the proportion of the addition reaction increases. For E isomers, the addition reaction at normal temperature is a large proportion and increases with the increase of temperature. In addition, the atmospheric life of two isomers has been calculated, and there are no other related reports. (2) the carcinogenicity of organic compounds to rodents is studied based on the DFT method. The QSAR prediction model is based on the CPDB tumor experiment database to select the most data of the liver tumor experimental data as the research object. By comparing the tumor experimental data of two sex rodents of male and female, it is found that there are obvious differences in various compounds, and in general, the female experimental animal shows the carcinogen to the male. Therefore, in consideration of the structural characteristics of the molecular structure, a cyclic compound was constructed for male rats, an acyclic compound against male rats, a ring compound against female rats, an acyclic compound to a female rat, a ring compound against male mice, an acyclic compound against male mice, and a cyclic compound against female mice. Eight quantitative prediction models of female mice, such as compound, were discussed in accordance with the model, combined with the existing knowledge. The prediction model constructed by the study can provide important theoretical support for the study of the effects of sex on carcinogenesis and the management of hazardous substances. (3) the study of organic matter to aquatic organisms is based on the DFT method. The acute toxicity of organic substances to the typical aquatic organisms (including fish and water fleas) of different trophic levels was selected in this chapter, and the QSAR prediction model was constructed based on the molecular structure optimized by the DFT method and compared. In the acute toxicity test of fish, the black head fish was the most commonly used experiment. One of the objects, therefore, has abundant experimental data and provides important data support for the acute toxicity prediction model of organic matter using the QSAR method. This paper collects and collects the 96 hour acute toxicity test data of 963 kinds of organic compounds to black head fish, and the molecules of all compounds on the level of MPWB1K/6-31+G (D, P) of the DFT method. The geometric structure optimization, the selection of the Dragon descriptor and the octanol water distribution coefficient logKow are selected as the alternative variables of the modeling. By means of genetic algorithm and multiple linear regression, a general model for predicting acute toxicity of black head fish is constructed with the help of the genetic algorithm and multiple linear regression. A local prediction model of acute toxicity of narcotic toxicants and toxic toxic substances was constructed. The large fleas belong to the world species, are the standard test organisms for toxicity test and have abundant experimental data. This chapter collects and collects the 48 hour acute toxicity test data of 479 kinds of organic compounds to the fleas, as well as on the MPWB1K/6-31+G (D, P) level of the DFT method. The geometric structure of the compound is optimized, the Dragon descriptor and logKow are selected as alternative variables of the modeling, and a general acute toxicity prediction model is constructed with the aid of genetic algorithm and multiple linear regression. In addition, the Verhaar classification framework is used as a reference for the classification of the toxic mechanism of the compounds using the toxicity ratio. The QSAR model was constructed, and the mechanism of each mechanism was discussed with the help of the model. Finally, the different toxicity mechanism of the organic matter to the black head fish and the large fleas was compared. The study found that the large fleas were more sensitive to the poison than the black head fish; besides aniline, thiophosphate was the same. Toxicities of the black headed fish and Daphnia magna are also different. They only show narcotic toxicity to the black headed fish, but show excessive toxicity to Daphnia magna.

【学位授予单位】：山东大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：X592
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本文编号：1868805