本文選題：艾滋病毒 + 二芳基三嗪類化合物��； 參考：《南華大學(xué)》2013年碩士論文

【摘要】：艾滋病(AIDS)是威脅人類健康的三大殺手之一，一直以來，對艾滋病的治療在世界范圍內(nèi)都是具有挑戰(zhàn)性的難題之一。艾滋病病毒(HIV)分為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復(fù)制的過程中，逆轉(zhuǎn)錄酶(RT)起著關(guān)鍵的作用，因此，逆轉(zhuǎn)錄酶抑制劑(RTIs)成為治療艾滋病藥物研制的重點(diǎn)。目前，已經(jīng)有多類抗艾滋病藥物用于臨床治療，然而HIV-1極易發(fā)生突變，，經(jīng)過一段時(shí)間后，由于產(chǎn)生了多種變異病毒株，這些藥物都失去了其應(yīng)有的藥效。HIV-1突變后，主要變異為以下幾種類型的病毒株：L100I、K103N、Y181C等。因此，對野生型和突變型病毒株均有抑制作用的藥物是目前抗HIV-1藥物研制的關(guān)鍵。 二芳基三嗪(DATA)類化合物是非核苷類逆轉(zhuǎn)錄酶抑制劑(NNRTIs)的一種，具有高效、高選擇性以及較好的抗耐藥性等優(yōu)點(diǎn)。鑒于本課題組已經(jīng)對DAPY類NNRTIs抗HIV-1病毒化合物以及其他類化合物的理論研究有了一定的成果，因此，本文以28個(gè)DATA類化合物為樣本，應(yīng)用分子力學(xué)方法、從頭算法對其進(jìn)行了結(jié)構(gòu)優(yōu)化計(jì)算，并采用多元線性回歸分析方法，從分子整體的理化性質(zhì)和(或)基團(tuán)的理化參數(shù)來考查化合物活性的定量構(gòu)效關(guān)系(QSAR)，在理論上分析該類化合物抗HIV-1可能的機(jī)制，為新型抗HIV-1藥物的設(shè)計(jì)和研制提供理論指導(dǎo)。 經(jīng)過一系列的分析，DATA類NNRTIs對野生型HIV-1和幾種主要突變型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，得到了相對于較早的研究結(jié)果較高的復(fù)相關(guān)系數(shù)。同時(shí)，通過改變DATA類化合物的分子結(jié)構(gòu)，可以提高其抑制活性。在DATA類抗野生型HIV-1化合物的分子結(jié)構(gòu)中，連接三嗪環(huán)與B環(huán)的X位置上的凈電荷量的增加有利于此類化合物抗HIV-1活性的提高，而并不是前人研究結(jié)果中所描述的X位置上為什么原子、什么基團(tuán)不是活性所必需的，只要是亞甲基的等排體就可以保持比較好的活性。該類化合物前線軌道能級差△E的增大、分子中吸電子基團(tuán)的引入以及分子體積適當(dāng)?shù)脑龃缶欣谄湟种艸IV-1活性的提高。其中，前線軌道能級差△E和分子的大小是影響DATA類化合物抗野生型HIV-1活性的主要因素。在DATA類抗突變型HIV-1化合物的分子結(jié)構(gòu)中，適當(dāng)?shù)脑龃蠓肿訖E圓度O、減小8號C原子的凈電荷量有利于其抗突變型L100I、K103N、Y181C HIV-1活性的提高；X位置上中心原子的Mulliken電荷量的減小有利于DATA類化合物抗突變型L100I、K103N HIV-1活性的提高；9號C原子Mulliken電荷量的減小有利于該類化合物抗突變型Y181CHIV-1活性的增強(qiáng)。同時(shí)，所建的QSAR模型中包含了相同的參數(shù)，通過調(diào)節(jié)影響該相同參數(shù)的分子的結(jié)構(gòu)，就可以同時(shí)改變DATA類化合物對三種突變型HIV-1的抑制活性，使得此類化合物在藥物研制方面更具實(shí)際應(yīng)用價(jià)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.
【學(xué)位授予單位】：南華大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2013
【分類號】：R512.91

【參考文獻(xiàn)】

相關(guān)期刊論文 前10條

1 邵學(xué)廣,蔡文生;化學(xué)信息學(xué)及其課程建設(shè)[J];大學(xué)化學(xué);2002年03期

2 楊挺;聶長明;林英武;;氨基喹啉類生物堿抗瘧原蟲活性的理論研究[J];分子科學(xué)學(xué)報(bào);2011年02期

3 石春雨;聶長明;劉慧杰;寧左云;;DAPY類化合物抑制野生型HIV-1活性的QSAR研究[J];分子科學(xué)學(xué)報(bào);2012年01期

4 范立新;回歸分析中多重共線性診斷方法[J];國外醫(yī)學(xué).衛(wèi)生學(xué)分冊;1994年01期

5 紀(jì)彩虹;;定量構(gòu)效關(guān)系的原理、方法及其研究進(jìn)展[J];甘肅聯(lián)合大學(xué)學(xué)報(bào)(自然科學(xué)版);2011年02期

6 魏洪源,羅順忠,劉國平,楊玉青,蔣樹斌;~(153)Sm骨腫瘤治療藥物配體結(jié)構(gòu)與生物活性相關(guān)性研究[J];核化學(xué)與放射化學(xué);2003年02期

7 熊遠(yuǎn)珍;陳芬兒;馮筱晴;;DATA類逆轉(zhuǎn)錄酶抑制劑的三維定量構(gòu)效關(guān)系[J];化學(xué)學(xué)報(bào);2006年16期

8 黃琦;康宏;張端峰;盛振;劉琦;朱瑞新;曹志偉;;基于配體、受體和復(fù)合物指紋的虛擬篩選方法比較[J];化學(xué)學(xué)報(bào);2011年05期

9 朱瑞新;王飛;劉琦;康廷國;;IOPY/ISPY類HIV-1逆轉(zhuǎn)錄酶抑制劑的定量構(gòu)效關(guān)系研究[J];化學(xué)學(xué)報(bào);2011年15期

10 馬雄威;;線性回歸方程中多重共線性診斷方法及其實(shí)證分析[J];華中農(nóng)業(yè)大學(xué)學(xué)報(bào)(社會(huì)科學(xué)版);2008年02期

相關(guān)博士學(xué)位論文 前2條

1 孫立力;電性距離矢量用于藥物定量構(gòu)效關(guān)系研究[D];重慶大學(xué);2004年

2 趙春燕;QSAR研究在生命分析化學(xué)和環(huán)境化學(xué)中的應(yīng)用[D];蘭州大學(xué);2006年

相關(guān)碩士學(xué)位論文 前1條

1 黃曉露;木質(zhì)素模型化合物熱解的微觀機(jī)理研究[D];重慶大學(xué);2012年

本文編號：1834434