DATA类化合物抗HIV-1活性的理论研究

发布时间：2018-05-02 15:14

本文选题：艾滋病毒 + 二芳基三嗪类化合物　；参考：《南华大学》2013年硕士论文

【摘要】：艾滋病(AIDS)是威胁人类健康的三大杀手之一，一直以来，对艾滋病的治疗在世界范围内都是具有挑战性的难题之一。艾滋病病毒(HIV)分为HIV-1型和HIV-2型，而大部分患者都是感染HIV-1型病毒所致病。在HIV-1复制的过程中，逆转录酶(RT)起着关键的作用，因此，逆转录酶抑制剂(RTIs)成为治疗艾滋病药物研制的重点。目前，已经有多类抗艾滋病药物用于临床治疗，然而HIV-1极易发生突变，，经过一段时间后，由于产生了多种变异病毒株，这些药物都失去了其应有的药效。HIV-1突变后，主要变异为以下几种类型的病毒株：L100I、K103N、Y181C等。因此，对野生型和突变型病毒株均有抑制作用的药物是目前抗HIV-1药物研制的关键。二芳基三嗪(DATA)类化合物是非核苷类逆转录酶抑制剂(NNRTIs)的一种，具有高效、高选择性以及较好的抗耐药性等优点。鉴于本课题组已经对DAPY类NNRTIs抗HIV-1病毒化合物以及其他类化合物的理论研究有了一定的成果，因此，本文以28个DATA类化合物为样本，应用分子力学方法、从头算法对其进行了结构优化计算，并采用多元线性回归分析方法，从分子整体的理化性质和(或)基团的理化参数来考查化合物活性的定量构效关系(QSAR)，在理论上分析该类化合物抗HIV-1可能的机制，为新型抗HIV-1药物的设计和研制提供理论指导。经过一系列的分析，DATA类NNRTIs对野生型HIV-1和几种主要突变型HIV-1病毒株均有一定的抑制作用，并且，在抗野生型HIV-1的QSAR模型中，得到了相对于较早的研究结果较高的复相关系数。同时，通过改变DATA类化合物的分子结构，可以提高其抑制活性。在DATA类抗野生型HIV-1化合物的分子结构中，连接三嗪环与B环的X位置上的净电荷量的增加有利于此类化合物抗HIV-1活性的提高，而并不是前人研究结果中所描述的X位置上为什么原子、什么基团不是活性所必需的，只要是亚甲基的等排体就可以保持比较好的活性。该类化合物前线轨道能级差△E的增大、分子中吸电子基团的引入以及分子体积适当的增大均有利于其抑制HIV-1活性的提高。其中，前线轨道能级差△E和分子的大小是影响DATA类化合物抗野生型HIV-1活性的主要因素。在DATA类抗突变型HIV-1化合物的分子结构中，适当的增大分子椭圆度O、减小8号C原子的净电荷量有利于其抗突变型L100I、K103N、Y181C HIV-1活性的提高；X位置上中心原子的Mulliken电荷量的减小有利于DATA类化合物抗突变型L100I、K103N HIV-1活性的提高；9号C原子Mulliken电荷量的减小有利于该类化合物抗突变型Y181CHIV-1活性的增强。同时，所建的QSAR模型中包含了相同的参数，通过调节影响该相同参数的分子的结构，就可以同时改变DATA类化合物对三种突变型HIV-1的抑制活性，使得此类化合物在药物研制方面更具实际应用价值。
[Abstract]:AIDS AIDS (AIDS) is one of the three killer threats to human health, and the treatment of AIDS is one of the most challenging problems all over the world. HIV is divided into HIV-1 and HIV-2, and most of the patients are infected with HIV-1 virus. In the process of HIV-1 replication, reverse transcriptase (RT) plays a key role. Therefore, reverse transcriptase inhibitor (HIV-1) has become the focus of drug development for AIDS. At present, there are many kinds of anti-AIDS drugs used in clinical treatment. However, HIV-1 is prone to mutation. After a period of time, due to the production of a variety of variant virus strains, these drugs have lost their due drug efficacy. HIV-1 mutation. The main mutations were the following types of virus strain: L100 Ignon K103NK181C and so on. Therefore, drugs that inhibit both wild and mutant virus strains are the key to the development of anti-HIV-1 drugs. Diaryltriazine DATAs are one of the non-nucleoside reverse transcriptase inhibitors (NNRTIss), which have the advantages of high efficiency, high selectivity and good resistance to drug resistance. Since our team has made some achievements in the theoretical study of DAPY class NNRTIs antiviral compounds and other kinds of compounds, we take 28 DATA class compounds as samples and apply molecular mechanics method. The ab initio algorithm is used to calculate its structure, and the multivariate linear regression analysis method is used. From the physicochemical properties of the molecular whole and / or the physicochemical parameters of the group, the quantitative structure-activity relationship of the compounds was studied, and the possible mechanism of the anti- HIV-1 of these compounds was analyzed theoretically, which provides theoretical guidance for the design and development of new anti- HIV-1 drugs. After a series of analyses, the data class NNRTIs can inhibit the wild-type HIV-1 and several major mutant HIV-1 virus strains to some extent, and in the QSAR model of anti-wild-type HIV-1, the complex correlation coefficient is higher than the earlier results. At the same time, the inhibitory activity of DATA compounds can be improved by changing their molecular structure. In the molecular structure of DATA type anti-wild-type HIV-1 compounds, the increase of net charge at the X position of triazine ring and B ring is beneficial to the increase of anti- activity of these compounds. But it is not the reason why the atom is in the X position, which group is not necessary for the activity, so long as it is the isoparbital of methylene, it can keep the better activity. The increase of frontier orbital energy difference E, the introduction of electron absorbing group and the proper increase of molecular volume are beneficial to the inhibition of HIV-1 activity. Among them, the frontier orbital energy difference E and molecular size are the main factors that affect the activity of DATA compounds against wild type HIV-1. In the molecular structure of DATA class anti-mutagenic HIV-1 compounds, Properly increasing the ellipticity of the molecule and decreasing the net charge of the 8C atom are beneficial to the increase of the HIV-1 activity of the mutagenic type L100IN K103NU Y181C and the decrease of the Mulliken charge of the center atom in the X position is favorable to the mutagenic L100IK103N HIV-1 activity of the DATA compounds. The decrease of the Mulliken charge of 9 C atom is beneficial to the enhancement of the mutagenic Y181CHIV-1 activity of this kind of compounds. At the same time, the QSAR model contains the same parameters. By adjusting the structure of the molecules that affect the same parameters, the inhibitory activity of DATA compounds to three mutant HIV-1 can be changed at the same time. This kind of compound has more practical application value in the field of drug development.
【学位授予单位】：南华大学
【学位级别】：硕士
【学位授予年份】：2013
【分类号】：R512.91

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