HIV-1整合酶全酶结构模拟及其抑制剂筛选
|
摘要
人类免疫缺陷病毒(human immunodeficiency virus,HIV)是引起艾滋病(acquired immunodeficiency syndrome,AIDS)蔓延的病原体,属于逆转录病毒科、慢病毒属中的灵长类免疫缺陷病毒亚属。从1981年美国发现首例AIDS至今,全世界约有5600万AIDS患者和HIV感染者,并已造成1390万人死亡,每天新增感染者1.6万例。
HIV的复制周期分为早期阶段的吸附、穿入、脱壳、逆转录、整合及后期阶段的病毒基因组复制、晚期转录、晚期翻译、装配、发芽成熟等。这些步骤对于病毒感染都是至关重要的,因而均成为了抗艾滋病病毒的重要靶点。截止至2006年8月,美国FDA批准使用的抗艾滋病药物共有29种,包括核苷类逆转录酶抑制剂、非核苷类逆转录酶抑制剂、蛋白酶抑制剂、融合抑制剂等共计4大类。尽管这些药物已成功用于治疗艾滋病感染,但由于病毒对此类药物表现出越来越严重的耐药性,临床上迫切需要寻找更多作用于不同靶点的抗病毒药物。
近年来,HIV-1整合酶(integrase,IN)成为一个新颖的靶点而受到人们重视。这是因为与蛋白酶和逆转录酶不同,整合酶在哺乳动物体内没有同源蛋白,因此有着更好的选择性。但相对于蛋白酶和逆转录酶,整合酶抑制剂的开发较为缓慢。直到2006年,整合酶抑制剂GS-9137进入临床研究阶段,2007年Raltegravir(MK-0518)被批准为第一个抑制整合酶的新药,才使得在整合酶抑制剂研究上取得了重大突破。
为了进一步开展基于HIV-1整合酶结构的抑制剂设计,首先必须深入了解HIV-1整合酶的结构和功能。目前蛋白质数据库(protein data bank,PDB)中有26个关于HIV-1整合酶的晶体结构,但仅仅是包含整合酶的单个结构域或其中的两个结构域,无整合酶全酶的晶体结构。因此,整合酶具体以何种聚合态发挥催化作用还不确定,人们对其结构和功能的认识还不够透彻。
本研究充分利用生物信息数据库和化学信息数据库中已有的HIV-1整合酶及其抑制剂的结构数据,综合运用分子模拟技术和计算机辅助药物设计的各种理论和方法,在HIV-1整合酶全酶晶体结构未知情况下,一方面从小分子结构出发,利用现有抑制剂的结构信息,找出分子中共同的作用模式,即构建药效团;另一方面,从已有的有关HIV-1整合酶晶体结构出发,构建HIV-1整合酶全酶及其与病毒DNA复合物的结构模型,并通过模拟不同作用机制的抑制剂在整合酶中的对接口袋,研究不同类型抑制剂与整合酶的结合模式和作用方式,进一步为基于结构的抗HIV-1整合酶的药物设计提供重要参考。同时开展基于药效团模型和分子对接的数据库筛选,以及实验研究。设计筛选新的HIV-1整合酶抑制剂,对发展治疗艾滋病的联合疗法具有十分重要的意义。
目的:构建出HIV-1整合酶全酶的结构、进一步明确HIV-1整合酶的催化机理及相应的催化位点,并在此基础之上筛选出结构新颖的HIV-1整合酶抑制剂。
方法:利用结构比对、同源模建的方法构建全长HIV-1整合酶二聚体结构,在此基础之上模拟出相应的四聚体模型,与已知的实验结果相互验证,进一步确定整合酶发挥催化作用时的聚合态;利用大分子对接、分子动力学模拟的方法构建整合酶-病毒DNA复合物结构模型,从而确定整合酶的活性部位以及与活性相关的重要残基;选取有代表性的整合酶抑制剂构建药效团模型;利用现有的HIV-1整合酶核心结构域的晶体结构构建抑制剂分子的对接口袋;基于上述构建的药效团模型及分子对接口袋对中药化学数据库(TCMD)进行虚拟筛选,寻找符合要求的化合物;通过分子动力学模拟的方法动态考察筛选出的化合物与整合酶的结合情况;在体外检测化合物的抗HIV-1活性。
结果:构建了HIV-1整合酶四聚体的结构模型以及整合酶二聚体-病毒DNA复合物的结构模型;计算得到“链转移”抑制剂的一个4点药效团模型,该模型包括3个氢键接受原子(Accept atom)和一个疏水中心(Hydrophobic);模拟了HIV-1整合酶核心结构域中“链转移”抑制剂的对接口袋模型;基于所建的4点药效团模型和分子对接口袋模型筛选中药化学数据库(TCMD),得到9个与模型匹配的化合物,分别为芸薹葡糖硫苷( glucobrassicin )、桂竹香苷(glucocheirolin)、葡萄糖糖芥苷(glucoerysolin)、屈曲花苷(glucoiberin)、萝卜硫苷(glucoraphanin)、旱金莲硫糖苷(glucotropaeolin)、黑芥子苷(sinigrin)、新芸薹苷(neoglucobrassicin)、白芥子苷(sinalbin),该类化合物均属于硫苷类化合物,具有相似的结构;分子动力学模拟结果也显示该类化合物能较好地与HIV-1整合酶核心结构域结合。
结论:
1文献显示HIV-1整合酶有两种可能的聚合形态,分别为二聚体和四聚体。本研究所构建的HIV-1整合酶四聚体结构表明,HIV-1整合酶以四聚体的形态发挥催化作用更合理。
2 HIV-1整合酶核心结构域应该有2个Mg2+的存在,即整合酶是通过双金属离子的作用机理发挥催化效应。
3整合过程中重要的两个过程“3′-加工”(与病毒DNA的作用位点)和“链转移”(与人体DNA的作用位点)在整合酶上占据不同的催化部位,但彼此位置相近。其中“3′-加工”的催化位点与晶体结构1QS4中小分子抑制剂占据的位点基本一致。
4对接结果显示,“链转移”抑制剂发挥催化作用的机理可能与螯合整合酶上重要的辅助因子Mg2+有关。
5所构建的4点药效团模型(包括三个氢键接受原子以及一个疏水中心)能较好的体现大多数现有“链转移”抑制剂中对活性起重要作用的药效特征元素。
6通过药效团筛选、对接筛选得到的9个化合物均为硫苷类化合物,它们大多数来源于十字花科植物(如板蓝根、大青叶),针对提取物的药理实验都显示出了抗菌、抗病毒、抗肿瘤、增加免疫力的作用,因此该类化合物有可能具有抗HIV的作用,但仍需进一步的实验验证。
Human immunodeficiency virus is the pathogen which provokes the spreading of acquired immunodeficiency syndrome(AIDS) belonging to the subgenus of primate immunodeficiency virus of ribodeoxy virus and lentivirus. From 1981 when the first AIDS was discovered in America to now, there have been about 56,000,000 HIV victims and infectors over the world, and it has caused 13,900,000 people to death while about 16,000 infectors are adding everyday.
HIV replicative cycle can be divided into the early stage including the absorbing, penetrating, uncoating, reverse transcriping, integrasing and the later stage of viral genome replication, advanced transcription, and so on. All these steps are so crucial to the infection that become the significant targets to the antivirus. Until August in 2006, there are 29 anti-HIV drug approved by FDA which include the nucleoside reverse transcriptase inhibitors, nonnucleoside reverse transcriptase inhibitors, protease inhibitors and fusion inhibitors. Although all of them have been successfully used to cure AIDS, the severe drug resistance makes it still ugernt to search for more new drugs in clinical which effect on different targets.
In recently years, the HIV-1 integrase becomes an attractive target to design new drugs. Different from protease and reverse transcriptase, the integrase has no counterpart in mammalian body, thus it has a better selectivity. But compared to the protease inhibitors and reverse transcriptase inhibitors, the designment of HIV-1 integrase inhibitors is relatively slow. As the inhibitor GS-9137 enters phaseⅠclinical in 2006 and raltegravir(MK-0518) was approaved to be the first new drug of integrase inhibitors in 2007, a significant breakthrough has been made in this field.
To further develop the designment of HIV-1 integrase inhibitors, it is necessary to deeply understand the structure and the function of HIV-1 integrase. At present, there are 26 crystal structures of HIV-1 integrase in the protein data bank, which include single domain or two domains of it, but none of them is the holoenzyme structure of HIV-1 integrase. Thus, it is not sure that what multimer the HIV-1 integrase may adopt to play a catalytic role, and the understanding about the structure and the function of HIV-1 integrase is still ambiguous.
This research makes full use of the structures of HIV-1 integrase and its inhibitors in the biological information database and chemical information database. Under the circumstances of the absent informations of the HIV-1 integrase holoenzyme, this acticle comprehensively use the molecular simulation technologies and theories of computer aided drug design(CADD) to carry out the investigation in two aspects. On one hand, constructing the pharmacophore of HIV-1 integrase inhibitors is accomplished based on the existing inhibitors, on the other hand building the HIV-1 integrase holoenzyme and the complex of HIV-1 integrase-viral DNA on the basis of the existing crystal structures of HIV-1 integrase. Besides, a docking pocket in the core domain of HIV-1 integrase is constructed to fulfill the docking test between HIV-1 integrase and its different inhibitors, then the docking results may offer useful informations which can provide important basis to develop the desigment of HIV-1 integrase inhibitors and the virtual screening based on the pharmacophore model and the docking pocket. Designment and screening of new HIV-1 integrase inhibitors also have importment significance to promote the combination therapy of curing AIDS.
Objective: To simulate the heloenzyme structure of HIV-1 integrase, clarify the catalytic mechanism and active site of HIV-1 integrase,and then to screen new integrase inhibitors based on it.
Methods: 1)The complete dimer of HIV-1 integrase was builded through structure comparison and homology modeling, and then the corresponding tetramer model was constructed to ascertain the multimer of HIV-1 integrase while it worked. 2) The complex of integrase-viral DNA was built through macromolecule docking and dynamics simulation to determine the active site and significant residues in the integrase. 3) To construct the pharmacophore of HIV-1integrase inhibitors based on the existing inhibitors. 4) To construct the docking pocket using the existing crystal structures of HIV-1 integrase. 5) Screening the Traditional Chinese Medicine Database to search for the suitable compounds based on the pharmacophore model and the docking pocket. 6) Through the molecular dynamics simulation, the binding informations is investigated between the HIV-1 integrase and the ligands. 7) Pharmacological tests of anti-HIV activity in vitro to the compounds.
Results: The tetramer model of HIV-1 integrase and the complex of its dimer with viral DNA have been constructured. A pharmacophore of the strand transfer inhibitors of HIV-1 integrase with three accept atoms and a hydrophobic center has been constructed. Based on the pharmacophore model and the docking model, 9 suitable ligands from TCMD have been received after screening. They were glucobrassicin, glucocheirolin, glucoerysolin, glucoiberin, glucoraphanin, glucotropaeolin, sinigrin, neoglucobrassicin, sinalbin which had similar structures belonging to the thioglycosides. Besides, the molecular dynamics results truely showed the stubborn binding between the catalytic domain of HIV-1 integrase and these ligands.
Conclusion:
1 The existing research shows that the HIV-1 integrase may play a catalytic role as its dimer or tetramer. In this article we believe that the HIV-1 integrase is possible to play a catalytic role as its tetramer.
2 It is possible that there are two Mg2+ existing in the catalytic domain of integrase. In other words, the integrase catalyze the whole reactions with a two ions mechanism.
3 Two sinificant binding sites in the HIV-1 integrase of the 3′-processing(the viral DNA binding site) and the strand transfer(the human DNA binding site) are approximate but different, and the catalytic site of 3′-processing occupy the same position as the inhibitor of HIV-1 integrase in the crystal structure of 1QS4.
4 The docking results show that chelating the important cofactor Mg2+ may be the inhibition mechanism of the strand transfer inhibitors.
5 The pharmacophore model constructed with three accept atoms and a hydrophobic center may represent the significant features of most strand transfer inhibitors which are proved to be effective.
6 The 9 compounds obtained through virtual screening are belonging to the thioglycosides, most of which are extracted from the cruciferae plants, such as isatis indigotica, folium isatidis. Plenty of the extractions from these plants with antibiosis, antivirus, antitumor and immunity improvement have been discovered through the pharmacological tests. Thus, the 9 compounds obtained after screening are possible to play a role of anti- HIV.
HIV的复制周期分为早期阶段的吸附、穿入、脱壳、逆转录、整合及后期阶段的病毒基因组复制、晚期转录、晚期翻译、装配、发芽成熟等。这些步骤对于病毒感染都是至关重要的,因而均成为了抗艾滋病病毒的重要靶点。截止至2006年8月,美国FDA批准使用的抗艾滋病药物共有29种,包括核苷类逆转录酶抑制剂、非核苷类逆转录酶抑制剂、蛋白酶抑制剂、融合抑制剂等共计4大类。尽管这些药物已成功用于治疗艾滋病感染,但由于病毒对此类药物表现出越来越严重的耐药性,临床上迫切需要寻找更多作用于不同靶点的抗病毒药物。
近年来,HIV-1整合酶(integrase,IN)成为一个新颖的靶点而受到人们重视。这是因为与蛋白酶和逆转录酶不同,整合酶在哺乳动物体内没有同源蛋白,因此有着更好的选择性。但相对于蛋白酶和逆转录酶,整合酶抑制剂的开发较为缓慢。直到2006年,整合酶抑制剂GS-9137进入临床研究阶段,2007年Raltegravir(MK-0518)被批准为第一个抑制整合酶的新药,才使得在整合酶抑制剂研究上取得了重大突破。
为了进一步开展基于HIV-1整合酶结构的抑制剂设计,首先必须深入了解HIV-1整合酶的结构和功能。目前蛋白质数据库(protein data bank,PDB)中有26个关于HIV-1整合酶的晶体结构,但仅仅是包含整合酶的单个结构域或其中的两个结构域,无整合酶全酶的晶体结构。因此,整合酶具体以何种聚合态发挥催化作用还不确定,人们对其结构和功能的认识还不够透彻。
本研究充分利用生物信息数据库和化学信息数据库中已有的HIV-1整合酶及其抑制剂的结构数据,综合运用分子模拟技术和计算机辅助药物设计的各种理论和方法,在HIV-1整合酶全酶晶体结构未知情况下,一方面从小分子结构出发,利用现有抑制剂的结构信息,找出分子中共同的作用模式,即构建药效团;另一方面,从已有的有关HIV-1整合酶晶体结构出发,构建HIV-1整合酶全酶及其与病毒DNA复合物的结构模型,并通过模拟不同作用机制的抑制剂在整合酶中的对接口袋,研究不同类型抑制剂与整合酶的结合模式和作用方式,进一步为基于结构的抗HIV-1整合酶的药物设计提供重要参考。同时开展基于药效团模型和分子对接的数据库筛选,以及实验研究。设计筛选新的HIV-1整合酶抑制剂,对发展治疗艾滋病的联合疗法具有十分重要的意义。
目的:构建出HIV-1整合酶全酶的结构、进一步明确HIV-1整合酶的催化机理及相应的催化位点,并在此基础之上筛选出结构新颖的HIV-1整合酶抑制剂。
方法:利用结构比对、同源模建的方法构建全长HIV-1整合酶二聚体结构,在此基础之上模拟出相应的四聚体模型,与已知的实验结果相互验证,进一步确定整合酶发挥催化作用时的聚合态;利用大分子对接、分子动力学模拟的方法构建整合酶-病毒DNA复合物结构模型,从而确定整合酶的活性部位以及与活性相关的重要残基;选取有代表性的整合酶抑制剂构建药效团模型;利用现有的HIV-1整合酶核心结构域的晶体结构构建抑制剂分子的对接口袋;基于上述构建的药效团模型及分子对接口袋对中药化学数据库(TCMD)进行虚拟筛选,寻找符合要求的化合物;通过分子动力学模拟的方法动态考察筛选出的化合物与整合酶的结合情况;在体外检测化合物的抗HIV-1活性。
结果:构建了HIV-1整合酶四聚体的结构模型以及整合酶二聚体-病毒DNA复合物的结构模型;计算得到“链转移”抑制剂的一个4点药效团模型,该模型包括3个氢键接受原子(Accept atom)和一个疏水中心(Hydrophobic);模拟了HIV-1整合酶核心结构域中“链转移”抑制剂的对接口袋模型;基于所建的4点药效团模型和分子对接口袋模型筛选中药化学数据库(TCMD),得到9个与模型匹配的化合物,分别为芸薹葡糖硫苷( glucobrassicin )、桂竹香苷(glucocheirolin)、葡萄糖糖芥苷(glucoerysolin)、屈曲花苷(glucoiberin)、萝卜硫苷(glucoraphanin)、旱金莲硫糖苷(glucotropaeolin)、黑芥子苷(sinigrin)、新芸薹苷(neoglucobrassicin)、白芥子苷(sinalbin),该类化合物均属于硫苷类化合物,具有相似的结构;分子动力学模拟结果也显示该类化合物能较好地与HIV-1整合酶核心结构域结合。
结论:
1文献显示HIV-1整合酶有两种可能的聚合形态,分别为二聚体和四聚体。本研究所构建的HIV-1整合酶四聚体结构表明,HIV-1整合酶以四聚体的形态发挥催化作用更合理。
2 HIV-1整合酶核心结构域应该有2个Mg2+的存在,即整合酶是通过双金属离子的作用机理发挥催化效应。
3整合过程中重要的两个过程“3′-加工”(与病毒DNA的作用位点)和“链转移”(与人体DNA的作用位点)在整合酶上占据不同的催化部位,但彼此位置相近。其中“3′-加工”的催化位点与晶体结构1QS4中小分子抑制剂占据的位点基本一致。
4对接结果显示,“链转移”抑制剂发挥催化作用的机理可能与螯合整合酶上重要的辅助因子Mg2+有关。
5所构建的4点药效团模型(包括三个氢键接受原子以及一个疏水中心)能较好的体现大多数现有“链转移”抑制剂中对活性起重要作用的药效特征元素。
6通过药效团筛选、对接筛选得到的9个化合物均为硫苷类化合物,它们大多数来源于十字花科植物(如板蓝根、大青叶),针对提取物的药理实验都显示出了抗菌、抗病毒、抗肿瘤、增加免疫力的作用,因此该类化合物有可能具有抗HIV的作用,但仍需进一步的实验验证。
Human immunodeficiency virus is the pathogen which provokes the spreading of acquired immunodeficiency syndrome(AIDS) belonging to the subgenus of primate immunodeficiency virus of ribodeoxy virus and lentivirus. From 1981 when the first AIDS was discovered in America to now, there have been about 56,000,000 HIV victims and infectors over the world, and it has caused 13,900,000 people to death while about 16,000 infectors are adding everyday.
HIV replicative cycle can be divided into the early stage including the absorbing, penetrating, uncoating, reverse transcriping, integrasing and the later stage of viral genome replication, advanced transcription, and so on. All these steps are so crucial to the infection that become the significant targets to the antivirus. Until August in 2006, there are 29 anti-HIV drug approved by FDA which include the nucleoside reverse transcriptase inhibitors, nonnucleoside reverse transcriptase inhibitors, protease inhibitors and fusion inhibitors. Although all of them have been successfully used to cure AIDS, the severe drug resistance makes it still ugernt to search for more new drugs in clinical which effect on different targets.
In recently years, the HIV-1 integrase becomes an attractive target to design new drugs. Different from protease and reverse transcriptase, the integrase has no counterpart in mammalian body, thus it has a better selectivity. But compared to the protease inhibitors and reverse transcriptase inhibitors, the designment of HIV-1 integrase inhibitors is relatively slow. As the inhibitor GS-9137 enters phaseⅠclinical in 2006 and raltegravir(MK-0518) was approaved to be the first new drug of integrase inhibitors in 2007, a significant breakthrough has been made in this field.
To further develop the designment of HIV-1 integrase inhibitors, it is necessary to deeply understand the structure and the function of HIV-1 integrase. At present, there are 26 crystal structures of HIV-1 integrase in the protein data bank, which include single domain or two domains of it, but none of them is the holoenzyme structure of HIV-1 integrase. Thus, it is not sure that what multimer the HIV-1 integrase may adopt to play a catalytic role, and the understanding about the structure and the function of HIV-1 integrase is still ambiguous.
This research makes full use of the structures of HIV-1 integrase and its inhibitors in the biological information database and chemical information database. Under the circumstances of the absent informations of the HIV-1 integrase holoenzyme, this acticle comprehensively use the molecular simulation technologies and theories of computer aided drug design(CADD) to carry out the investigation in two aspects. On one hand, constructing the pharmacophore of HIV-1 integrase inhibitors is accomplished based on the existing inhibitors, on the other hand building the HIV-1 integrase holoenzyme and the complex of HIV-1 integrase-viral DNA on the basis of the existing crystal structures of HIV-1 integrase. Besides, a docking pocket in the core domain of HIV-1 integrase is constructed to fulfill the docking test between HIV-1 integrase and its different inhibitors, then the docking results may offer useful informations which can provide important basis to develop the desigment of HIV-1 integrase inhibitors and the virtual screening based on the pharmacophore model and the docking pocket. Designment and screening of new HIV-1 integrase inhibitors also have importment significance to promote the combination therapy of curing AIDS.
Objective: To simulate the heloenzyme structure of HIV-1 integrase, clarify the catalytic mechanism and active site of HIV-1 integrase,and then to screen new integrase inhibitors based on it.
Methods: 1)The complete dimer of HIV-1 integrase was builded through structure comparison and homology modeling, and then the corresponding tetramer model was constructed to ascertain the multimer of HIV-1 integrase while it worked. 2) The complex of integrase-viral DNA was built through macromolecule docking and dynamics simulation to determine the active site and significant residues in the integrase. 3) To construct the pharmacophore of HIV-1integrase inhibitors based on the existing inhibitors. 4) To construct the docking pocket using the existing crystal structures of HIV-1 integrase. 5) Screening the Traditional Chinese Medicine Database to search for the suitable compounds based on the pharmacophore model and the docking pocket. 6) Through the molecular dynamics simulation, the binding informations is investigated between the HIV-1 integrase and the ligands. 7) Pharmacological tests of anti-HIV activity in vitro to the compounds.
Results: The tetramer model of HIV-1 integrase and the complex of its dimer with viral DNA have been constructured. A pharmacophore of the strand transfer inhibitors of HIV-1 integrase with three accept atoms and a hydrophobic center has been constructed. Based on the pharmacophore model and the docking model, 9 suitable ligands from TCMD have been received after screening. They were glucobrassicin, glucocheirolin, glucoerysolin, glucoiberin, glucoraphanin, glucotropaeolin, sinigrin, neoglucobrassicin, sinalbin which had similar structures belonging to the thioglycosides. Besides, the molecular dynamics results truely showed the stubborn binding between the catalytic domain of HIV-1 integrase and these ligands.
Conclusion:
1 The existing research shows that the HIV-1 integrase may play a catalytic role as its dimer or tetramer. In this article we believe that the HIV-1 integrase is possible to play a catalytic role as its tetramer.
2 It is possible that there are two Mg2+ existing in the catalytic domain of integrase. In other words, the integrase catalyze the whole reactions with a two ions mechanism.
3 Two sinificant binding sites in the HIV-1 integrase of the 3′-processing(the viral DNA binding site) and the strand transfer(the human DNA binding site) are approximate but different, and the catalytic site of 3′-processing occupy the same position as the inhibitor of HIV-1 integrase in the crystal structure of 1QS4.
4 The docking results show that chelating the important cofactor Mg2+ may be the inhibition mechanism of the strand transfer inhibitors.
5 The pharmacophore model constructed with three accept atoms and a hydrophobic center may represent the significant features of most strand transfer inhibitors which are proved to be effective.
6 The 9 compounds obtained through virtual screening are belonging to the thioglycosides, most of which are extracted from the cruciferae plants, such as isatis indigotica, folium isatidis. Plenty of the extractions from these plants with antibiosis, antivirus, antitumor and immunity improvement have been discovered through the pharmacological tests. Thus, the 9 compounds obtained after screening are possible to play a role of anti- HIV.
引文
1黄秀艳,曾耀英.艾滋病发病学研进展与药物和疫苗研发新策略[J].中国病理生理杂志,2008, 24: 1861-1864
2傅婷婷,倪孟祥.核苷类抗艾滋病药物研发近况[J].药学进展,2007, 31: 211-216
3束梅英. HIV/AIDS药物治疗最新进展[J].中国制药信息,2008, 24: 10-13
4 Benedicte V M, Zeger D. HIV-1 integrase: an interplay between HIV-1 integrase, cellular and viral proteins[J]. AIDS, 2005, 7: 26-43
5 Zheng R L, Timothy M, Jenkins, et al. Zinc folds the N-terminal domain of HIV-1 integrase, promotes multimerization, and enhances catalytic activity [J]. Biochemistry, 1996, 93:13659-13664
6 Goldgur Y, Dydaf, Hickman A B, et al. Three new structures of the core domine of HIV-1 integrase:An activate site that binds magnesium [J]. Biochemistry, 1998, 95: 9150-9154.
7 Julian C H, Jolanta K, Larry J W, et al. Crystal structure of the HIV-1 integrase catalytic core and C-terminal domains: a model for viral DNA binding[J].Biochemistry, 2000, 97: 8233-8238
8 Kehlenbeck S, Betzu, Birkmann A, et al.Dihydroxythioph- enes are novel potent inhibitors of human immunodeficiency virus integrase with a diketo acid-like pharmacophore[J]. Virology, 2006, 80: 6883-6894
9 Johnson A A, Santos W, Pais G C , et al. Integration requires a specific interaction of the donor DNA terminal 5′-cytosine with glutamine 148 of the HIV-1integrase flexible loop [J]. Biochemistry, 2006, 281: 461-467
10 Diamond T L, Bushman F D. Division of labor within human immunodeficiency virus integrase complexes: determinant of catalisis and target DNA capture [J]. American Society for Microbiology, 2005, 79: 15376-15387
11 Billich A. S-1360(Shionogi-GlaxoSmithKline) [J]. Current Opinion in Investigational Drugs, 2003, 4: 206-209
1 Jennifer L, Gerton, Patrick O B. The core domain of HIV-1 integrase recognizes key features of its DNA substrates[J]. Biological Chemistry, 1997, 272: 25809-25815
2 Wang J Y, Ling H, Yang W, et al. Structure of a two-domain fragment of HIV-1 integrase:implications for domain organization in the intact protein[J]. EMBO, 2001, 20: 7333-7343
3 Goldgur Y, Graigie R, Cohen G H, et al. Structure of the HIV-1 integrase catalytic domain complexed with an inhibitor:A platform for antiviral drug design[J]. PNAS, 1999, 96: 13040-13043
4 Chen J C, Krucinski J, Miercke L J, et al. Crystal structure of the HIV-1 integrase catalytic core and C-terminal domains:A model for viral DNA binding[J]. Biochemistry, 2000, 97: 8233-8238
5 Maignan S, Guilloteau J P, Zhou L Q, et al. Crystal structures of the catalytic domain of HIV-1 integrase free and complexed with its metal cofactor: high level of similarity of the active site with other viral integrases[J]. Mol.Biol, 1998, 282: 359-368
6 Cai M, Zheng R, Caffrey M, et al. Solution structure of the N-terminal zinc binding domain of HIV-1 integrase[J]. Nature Structural Biology, 1997, 4:567-577
7 Jeffery J G, Stewart M, Chu W, et al. Protein–Protein dockingwith simultaneous optimization of rigid-body displacement and side-chain conformations[J]. J. Mol. Biol, 2003, 331: 281-299
8 Michael P A. Introduction to molecular dynamics simulation[J]. Computational Soft Matter, 2004, 23: 1-28
9 Makoto T J, Tetsu N, Yousuke O, et al. Protein explorer: A petaflops special-purpose computer for molecular dynamics simulations[J]. Genome Informatics, 2002, 13: 461-462
10 Zheng L L, Jenkins T M, Craigie A R. Zinc folds the N-terminal domain of HIV-1 integrase, promotes multimerization,and enhances catalytic activity[J]. Biochemistry, 1996, 93: 13659-13664
11 Karki R G, Tang Yun, Burke T R, et al. Model of full-length HIV-1 integrase complexed with viral DNA as template for anti-HIV drug design[J]. Computer-aided molecular design, 2004, 18: 739-760
12 Rice P A, Baker T A. Comparative architecture of transposase and integrase complexes[J]. Nature, 2001, 8: 302-307
1 Do J K, Sang K L, You T O, et al. Minimal core domain of HIV-1 integrase for biological activity[J]. Molecules and Cells, 1999, 10: 96-101
2胡建平,柯国涛,常珊等.用分子对接方法研究HIV-1整合酶与病毒DNA的结合模式[J].高等学校化学学报, 2008, 7: 1432-1437
3王丽东,王存新.金属离子对HIV-1整合酶与硫氮硫扎平抑制剂作用模式影响的分子模拟研究[J].化学学报,2008, 66: 817-822
4 Goldgur Y, Graigie R, Cohen G H, et al. Structure of the HIV-1 integrase catalytic domain complexed with aninhibitor:A platform for antiviral drug design[J]. PNAS, 1999, 96: 13040-13043
5 Renisio J G, Cosquer S, Cherrak I,et al. Pre-organized structure of viral DNA at the binding-processing site of HIV-1 integrase[J]. Nucleic Acids Research, 2005, 33:1970-1981
6 Bujacz G, Alexandratos J, Wlodawer A, et al. Binding of different divalent cations to the active site of avian sarcoma virus integrase and their effects on enzymatic activity[J]. Biochemistry, 1997, 272: 18161-18168
7 Steriniger M, Adams C D, Marko J F, et al. Defining characteristics of Tn5 transposase non-specific DNA binding[J]. Nucleic Acids Research, 2006, 34: 2820-2832
8 Nowotny M, Gaidamakov S A, Crouch R J, et al. Crystal structures of RNase H bound to an RNA/DNA hybrid: substrate specificity and metal-dependent catalysis[J]. Cell, 2005, 121: 1005-1016
9 Jerome W, Ian T C, David K C. A three-dimentional model of human immunodeficiency virus type 1 integrase complex[J]. Computer-aided molecular design, 2005, 19: 301-217
10 Rice P A, Baker T A. Comparative architecture of transposa- se and integrase complexes[J]. Nature, 2001, 8: 302-307
11 Czyz A, Stillmock K A, Hazuda D J, et al. Dissecting Tn5 Transposition using HIV-1 integrase diketoacid inhibitors[J]. Biochemistry, 2007, 46: 10776-10789
12 Johnson A A, Marchand C, Patil S S.Probing HIV-1integrase inhibitor binding sites with position-specific integrase-DNA crosslinking assays[J]. Molecular Pharmacology Fast Forward, 2007, 71: 893-901
13 TimothyS, Patrick O B. Mapping features of HIV-1integrase near selected sites on viral and target DNA molecules in an active enzyme-DNA complex by photo-cross-linking[J]. Biochemistry, 1997, 36: 10655-10665
14 Barreca M L, Lee K W, Chimirri A, et al. Molecular dynamics studies of the wild-type and double mutant HIV-1 integrase complexed with the 5CITEP inhibitor:mechanism for inhibition and drug resistance[J]. Biophysical, 2003, 84: 1450-1463
15 Galburt E A, Stoddard B L. Catalytic mechanisms of restriction and homing endonucleases[J]. Biochemistry, 2002, 41: 13851-13860
16 Klumpp K, Hang J Q, Rajendran S, et al. Two-metal ion mechanism of RNA cleavage by HIV RNase H and mechanism-based design of selective HIV RNase H inhibitors[J]. Nucleic Acids Research, 2003, 31: 6852-6859
1 Joseph D, Carthy M, Baber J C, et al. Lead optimization via high-throughput molecular docking[J]. BioMed, 2007, 10: 264-274
2胡建平,常珊,陈慰祖等. HIV-1整合酶与抑制剂LCA的结合模式及抗药性研究[J].中国科学B辑:化学,2007, 37: 279-287
3宋伟,陈慰祖,张小轶等.用分子对接方法预测HIV-1整合酶与金精三羧酸抑制剂的相互作用[J].化学物理学报,2003, 16: 257-260
4李爱秀.中药“药效团药性假说”的提出[J].天津药学, 2007, 19: 41-44
5徐筱杰,侯廷军等.计算机辅助药物分子设计[M].北京:化学工业出版社,2004
6 Allison A J, Christophe M, Sachindra S P, et al. Probing HIV-1 integrase inhibitor binding sites with position- specific integrase-DNA cross-linking assays[J]. Molecular Pharmacology, 2007, 71: 893-901
7 Daria J H, Neville J A, Robert P G, et al. A naphathyridine carboxamide provides evidence for discortdant resistance between mechanistically identical inhibitors of HIV-1 integrase[J]. Biochemistry, 2004, 101: 11233-11238
8 Markowitz M, Morales R J, Nguyen B Y, et al. Antiretroviral activity, pharmacokinetics, and tolerability of MK-0518 a novel inhibitor of HIV-1 integrase, dosed as monotherapyfor 10 days in treatment-na?ve HIV-1 infected individuals[J]. Acquir Immune Defic Syndr, 2006, 5: 509-515
9 Kodama E, Shimura K, Sakagami Y. In vitro antiviral active- ty and resistance profile of a novel HIV integrase inhibitor JTK-303/GS-9137. 2006, San Francisco,California:H-254
1 Walter W P, Stahl M T, Murcko M A. Virtual screening-an overview[J]. Drug Discov. Today, 1998, 3: 160-178
2周家驹,谢桂荣,严新建.中药原植物化学成分手册[M].北京:化学工业出版社,2004, 9
3杨二冰,李正名.药物分子设计中的Lipinski规则[J].化学通报,2006, 69: 16-19
4 Leech J, Prins J F, Hermans J. SMD: visual steering of molecular dynamics for protein design[J]. Computational Science & Engineering, 1996, 3: 38 -45
5张玉松,王大燕,徐红等.假病毒的最新应用研究进展[J].医学研究杂志,2008, 37: 116-118
6曹颖莉,郭颖.应用假病毒技术研究HIV-1复制抑制剂[J].药理学报,2008, 43: 253-258
7郭颖,曹颖莉.以H5N1高致病禽流感病毒血凝素蛋白为靶标的药理筛选模型的建立[J].中国药理通讯,2007, 24: 46
8崔卓,王颖,康廷国.板蓝根有效成分质量研究[J].辽宁中医杂志, 2004, 31:692
9彭少平,顾振纶.板蓝根化学成分、药理作用研究进展[J].中国野生植物资源, 2005, 24: 4-7
10李鲜,陈昆松,张明方等.十字花科植物中硫代葡萄糖苷的研究进展[J].园艺学报, 2006, 33: 675-679
1傅婷婷,倪孟祥.核苷类抗艾滋病药物研发近况[J].药学进展,2007, 31: 211-216
2 Kehlenbeck S, Betz U, Birkmann A, et al. Dihydroxythioen- es are novel potent inhibitors of human immunodeficiency virus integrase with a diketo acid-like pharmacophore[J]. Virology, 2006, 80: 6883-6894
3 Johnson A A,Santos W, Pais G C G, et al.Integration requires a specific interaction of the donor DNA terminal 5′-cytosine with glutamine 148 of the HIV-1integrase flexible loop[J]. Biochemistry, 2006, 281: 461-467
4 Diamond T L, Bushman F D.Division of labor within human immunodeficiency virus integrase complexes:Determinant of catalisis and target DNA capture [J]. American Society for Microbiology, 2005, 79: 15376-15387
5 Fesen M R, Kohn K W, Leteurtre F, et al .Inhibitors of human immunodeficiency virus integrase [J]. Pharmacology, 1993, 90: 2399-2403
6 Drake R R, Neamati N, Hong H X, et al. Identification of a nucleotide binding site in HIV-1 integrase [J]. Biochemistry, 1998, 95: 4170-4175
7 Chi G, Neamati N, Nair V. Inhibition of the strand transfer step of HIV 1 integrase by non-natural dinucleotide [J]. Bioorg Med Chem Lett, 2004, 14: 4815-4817
8 Huang S L, Huang P L, Huang P L, et al. Inhibitor of theintegrase of the immunpdeficiency virus(HIV) type by anti- HIV plant proteins MAP30 and GAP31 [J]. Biochemistry, 1995, 92: 8818-8822
9 Gleenberg I O, Avidan O, Goldgur Y, et al. Peptides derived from the reverse transcriptase of human immunodeficiency virus type 1 as novel inhibitors of the viral integrase [J]. Biological chimistry, 2005, 280: 21987–21996
10 Goldgur Y, Craigie R, Cohen G H, et al. Structure of the HIV-1 integrase catalytic domain complexed with an inhibit- or: A platform for antiviral drug design [J]. Biochemistry, 1999, 96: 13040-13043
11 Barreca M L,Lee K W,Chimirri A, et al. Molecular dynamics studies of the wild-type and double mutant HIV-1 integrase complexed with the 5CITEP inhibitor: mechanism for inhibition and drug resistance [J]. Biophysical, 2003, 84: 1450-1463
12 Deprez E, Barbes S, Kolaski M, et al. Mechanism of HIV-1 integrase inhibition by styrylquinoline derivatives in vitro [J]. Molecular pharmacology, 2004, 65: 85-98
13 Ma X H,Zhang X Y,Tan J J,et al.Exploring binding mode for styrylquinoline HIV-1 integrase inhibitors using comparative molecular field analysis and docking studies [J]. Acta pharmacologica sinica, 2004, 25: 950-958
14 Semenova E A,Johonson A A,Marchand C, et al. Preferential inhibition of the magnesium-dependent strand transfer reaction of HIV-1 Integrase byα-Hydroxytropolones [J].Molecular pharmacology, 2006, 69: 1454-1460
15 Kehlenbeck S,Betz U,Birkmann I A,et al. Dihydroxythioph- enes are novel potent inhibitors of human immunodeficiency virus integrase with a diketo acid-like pharmacophore [J]. Virology, 2006, 80: 6883-6894
16 Hazuda D J, Anthony N J,Gomez R P, et al.A naphthyridine carboxamide provides evidence for discordant resistance between mechanistically identical inhibitors of HIV-1 integrase [J]. Biochemistry, 2004, 101:11233-11238
17 Hombrouck A, Hantson A, Remoortel B V, et al. Selection of human immunodeficiency virus type 1 resistance against the pyranodipyrimidine V-165 points to a multimodal mechanism of action [J]. Antimicrobial chemotherapy, 2007, 59: 1084–1095
1 Waszkowycz T D, Perkins R A, Sykes J L. Large-scale virtual screening for discovering leads in the postgenomic era[J]. IBM Systems Journal, 2001, 40: 360-376
2 John T K. Making virtual screening a reality[J]. PNAS, 2003, 100: 6902-6903
3徐筱杰,侯廷军等.计算机辅助药物分子设计[M].北京:化学工业出版社,2004
4郝方,张雪莲,张顺宝等.生物新技术在新药研发中的进展与展望[J].宁夏医学杂志,2005,27:142-143
5 Schellhammer I, Rarey M, Trix X. Structure-based molecule indexing for large-scare virtual screening in sublinear time[J]. Comp.Aided Mol Design, 2007, 21: 223-238
6 Kuntz I D. Structure-based strategies for drug design and discovery[J]. Science, 1992, 257: 1078-1082
7 Diane J, Mc C. Computational approaches to structure-based ligand design[J]. Pharmacology and Therapeutics, 1999, 84: 179-191
8 Bartosz A, Grzybowski, Alexey V, et al. Combinatorial computational methord gives new picomolar ligands for a known enzyme[J]. PNAS, 2002, 99: 1270-1273
9 Martin Y C. 3D database searching in drug design[J]. Med Chem, 1992, 35: 2145-2154
10 Marriott D P, Dougall I G, Meghani P, et al. Lead generation using pharmacophore mapping and three-dimensionaldatabase searching: application to muscarinic M(3) receptor antagonists[J]. Med Chem, 1999, 42: 3210-3216
11 Yasuhisa K. Mesangial cell proliferation inhibitors for the treatment of proliferative glomerular disease[J]. Medicinal Research Reviews, 2002, 23: 15-31
12 Winkler D A, Burden F R. Application of neural networks to large dataset QSAR, virtual screening, and library design[J]. Methods Mol Biol, 2002, 201: 325-367
13范志金,王玲秀,陈俊鹏等.新磺酰脲类除草剂NK#94827的除草活性[J].中国农学通报, 2004, 20: 198-200
14 Beresford A P, Selick H E, Tarbit M H. The emerging importance of predictive ADME simulation in drug discovery[J]. Drug discover today, 2002, 7: 109-116
2傅婷婷,倪孟祥.核苷类抗艾滋病药物研发近况[J].药学进展,2007, 31: 211-216
3束梅英. HIV/AIDS药物治疗最新进展[J].中国制药信息,2008, 24: 10-13
4 Benedicte V M, Zeger D. HIV-1 integrase: an interplay between HIV-1 integrase, cellular and viral proteins[J]. AIDS, 2005, 7: 26-43
5 Zheng R L, Timothy M, Jenkins, et al. Zinc folds the N-terminal domain of HIV-1 integrase, promotes multimerization, and enhances catalytic activity [J]. Biochemistry, 1996, 93:13659-13664
6 Goldgur Y, Dydaf, Hickman A B, et al. Three new structures of the core domine of HIV-1 integrase:An activate site that binds magnesium [J]. Biochemistry, 1998, 95: 9150-9154.
7 Julian C H, Jolanta K, Larry J W, et al. Crystal structure of the HIV-1 integrase catalytic core and C-terminal domains: a model for viral DNA binding[J].Biochemistry, 2000, 97: 8233-8238
8 Kehlenbeck S, Betzu, Birkmann A, et al.Dihydroxythioph- enes are novel potent inhibitors of human immunodeficiency virus integrase with a diketo acid-like pharmacophore[J]. Virology, 2006, 80: 6883-6894
9 Johnson A A, Santos W, Pais G C , et al. Integration requires a specific interaction of the donor DNA terminal 5′-cytosine with glutamine 148 of the HIV-1integrase flexible loop [J]. Biochemistry, 2006, 281: 461-467
10 Diamond T L, Bushman F D. Division of labor within human immunodeficiency virus integrase complexes: determinant of catalisis and target DNA capture [J]. American Society for Microbiology, 2005, 79: 15376-15387
11 Billich A. S-1360(Shionogi-GlaxoSmithKline) [J]. Current Opinion in Investigational Drugs, 2003, 4: 206-209
1 Jennifer L, Gerton, Patrick O B. The core domain of HIV-1 integrase recognizes key features of its DNA substrates[J]. Biological Chemistry, 1997, 272: 25809-25815
2 Wang J Y, Ling H, Yang W, et al. Structure of a two-domain fragment of HIV-1 integrase:implications for domain organization in the intact protein[J]. EMBO, 2001, 20: 7333-7343
3 Goldgur Y, Graigie R, Cohen G H, et al. Structure of the HIV-1 integrase catalytic domain complexed with an inhibitor:A platform for antiviral drug design[J]. PNAS, 1999, 96: 13040-13043
4 Chen J C, Krucinski J, Miercke L J, et al. Crystal structure of the HIV-1 integrase catalytic core and C-terminal domains:A model for viral DNA binding[J]. Biochemistry, 2000, 97: 8233-8238
5 Maignan S, Guilloteau J P, Zhou L Q, et al. Crystal structures of the catalytic domain of HIV-1 integrase free and complexed with its metal cofactor: high level of similarity of the active site with other viral integrases[J]. Mol.Biol, 1998, 282: 359-368
6 Cai M, Zheng R, Caffrey M, et al. Solution structure of the N-terminal zinc binding domain of HIV-1 integrase[J]. Nature Structural Biology, 1997, 4:567-577
7 Jeffery J G, Stewart M, Chu W, et al. Protein–Protein dockingwith simultaneous optimization of rigid-body displacement and side-chain conformations[J]. J. Mol. Biol, 2003, 331: 281-299
8 Michael P A. Introduction to molecular dynamics simulation[J]. Computational Soft Matter, 2004, 23: 1-28
9 Makoto T J, Tetsu N, Yousuke O, et al. Protein explorer: A petaflops special-purpose computer for molecular dynamics simulations[J]. Genome Informatics, 2002, 13: 461-462
10 Zheng L L, Jenkins T M, Craigie A R. Zinc folds the N-terminal domain of HIV-1 integrase, promotes multimerization,and enhances catalytic activity[J]. Biochemistry, 1996, 93: 13659-13664
11 Karki R G, Tang Yun, Burke T R, et al. Model of full-length HIV-1 integrase complexed with viral DNA as template for anti-HIV drug design[J]. Computer-aided molecular design, 2004, 18: 739-760
12 Rice P A, Baker T A. Comparative architecture of transposase and integrase complexes[J]. Nature, 2001, 8: 302-307
1 Do J K, Sang K L, You T O, et al. Minimal core domain of HIV-1 integrase for biological activity[J]. Molecules and Cells, 1999, 10: 96-101
2胡建平,柯国涛,常珊等.用分子对接方法研究HIV-1整合酶与病毒DNA的结合模式[J].高等学校化学学报, 2008, 7: 1432-1437
3王丽东,王存新.金属离子对HIV-1整合酶与硫氮硫扎平抑制剂作用模式影响的分子模拟研究[J].化学学报,2008, 66: 817-822
4 Goldgur Y, Graigie R, Cohen G H, et al. Structure of the HIV-1 integrase catalytic domain complexed with aninhibitor:A platform for antiviral drug design[J]. PNAS, 1999, 96: 13040-13043
5 Renisio J G, Cosquer S, Cherrak I,et al. Pre-organized structure of viral DNA at the binding-processing site of HIV-1 integrase[J]. Nucleic Acids Research, 2005, 33:1970-1981
6 Bujacz G, Alexandratos J, Wlodawer A, et al. Binding of different divalent cations to the active site of avian sarcoma virus integrase and their effects on enzymatic activity[J]. Biochemistry, 1997, 272: 18161-18168
7 Steriniger M, Adams C D, Marko J F, et al. Defining characteristics of Tn5 transposase non-specific DNA binding[J]. Nucleic Acids Research, 2006, 34: 2820-2832
8 Nowotny M, Gaidamakov S A, Crouch R J, et al. Crystal structures of RNase H bound to an RNA/DNA hybrid: substrate specificity and metal-dependent catalysis[J]. Cell, 2005, 121: 1005-1016
9 Jerome W, Ian T C, David K C. A three-dimentional model of human immunodeficiency virus type 1 integrase complex[J]. Computer-aided molecular design, 2005, 19: 301-217
10 Rice P A, Baker T A. Comparative architecture of transposa- se and integrase complexes[J]. Nature, 2001, 8: 302-307
11 Czyz A, Stillmock K A, Hazuda D J, et al. Dissecting Tn5 Transposition using HIV-1 integrase diketoacid inhibitors[J]. Biochemistry, 2007, 46: 10776-10789
12 Johnson A A, Marchand C, Patil S S.Probing HIV-1integrase inhibitor binding sites with position-specific integrase-DNA crosslinking assays[J]. Molecular Pharmacology Fast Forward, 2007, 71: 893-901
13 TimothyS, Patrick O B. Mapping features of HIV-1integrase near selected sites on viral and target DNA molecules in an active enzyme-DNA complex by photo-cross-linking[J]. Biochemistry, 1997, 36: 10655-10665
14 Barreca M L, Lee K W, Chimirri A, et al. Molecular dynamics studies of the wild-type and double mutant HIV-1 integrase complexed with the 5CITEP inhibitor:mechanism for inhibition and drug resistance[J]. Biophysical, 2003, 84: 1450-1463
15 Galburt E A, Stoddard B L. Catalytic mechanisms of restriction and homing endonucleases[J]. Biochemistry, 2002, 41: 13851-13860
16 Klumpp K, Hang J Q, Rajendran S, et al. Two-metal ion mechanism of RNA cleavage by HIV RNase H and mechanism-based design of selective HIV RNase H inhibitors[J]. Nucleic Acids Research, 2003, 31: 6852-6859
1 Joseph D, Carthy M, Baber J C, et al. Lead optimization via high-throughput molecular docking[J]. BioMed, 2007, 10: 264-274
2胡建平,常珊,陈慰祖等. HIV-1整合酶与抑制剂LCA的结合模式及抗药性研究[J].中国科学B辑:化学,2007, 37: 279-287
3宋伟,陈慰祖,张小轶等.用分子对接方法预测HIV-1整合酶与金精三羧酸抑制剂的相互作用[J].化学物理学报,2003, 16: 257-260
4李爱秀.中药“药效团药性假说”的提出[J].天津药学, 2007, 19: 41-44
5徐筱杰,侯廷军等.计算机辅助药物分子设计[M].北京:化学工业出版社,2004
6 Allison A J, Christophe M, Sachindra S P, et al. Probing HIV-1 integrase inhibitor binding sites with position- specific integrase-DNA cross-linking assays[J]. Molecular Pharmacology, 2007, 71: 893-901
7 Daria J H, Neville J A, Robert P G, et al. A naphathyridine carboxamide provides evidence for discortdant resistance between mechanistically identical inhibitors of HIV-1 integrase[J]. Biochemistry, 2004, 101: 11233-11238
8 Markowitz M, Morales R J, Nguyen B Y, et al. Antiretroviral activity, pharmacokinetics, and tolerability of MK-0518 a novel inhibitor of HIV-1 integrase, dosed as monotherapyfor 10 days in treatment-na?ve HIV-1 infected individuals[J]. Acquir Immune Defic Syndr, 2006, 5: 509-515
9 Kodama E, Shimura K, Sakagami Y. In vitro antiviral active- ty and resistance profile of a novel HIV integrase inhibitor JTK-303/GS-9137. 2006, San Francisco,California:H-254
1 Walter W P, Stahl M T, Murcko M A. Virtual screening-an overview[J]. Drug Discov. Today, 1998, 3: 160-178
2周家驹,谢桂荣,严新建.中药原植物化学成分手册[M].北京:化学工业出版社,2004, 9
3杨二冰,李正名.药物分子设计中的Lipinski规则[J].化学通报,2006, 69: 16-19
4 Leech J, Prins J F, Hermans J. SMD: visual steering of molecular dynamics for protein design[J]. Computational Science & Engineering, 1996, 3: 38 -45
5张玉松,王大燕,徐红等.假病毒的最新应用研究进展[J].医学研究杂志,2008, 37: 116-118
6曹颖莉,郭颖.应用假病毒技术研究HIV-1复制抑制剂[J].药理学报,2008, 43: 253-258
7郭颖,曹颖莉.以H5N1高致病禽流感病毒血凝素蛋白为靶标的药理筛选模型的建立[J].中国药理通讯,2007, 24: 46
8崔卓,王颖,康廷国.板蓝根有效成分质量研究[J].辽宁中医杂志, 2004, 31:692
9彭少平,顾振纶.板蓝根化学成分、药理作用研究进展[J].中国野生植物资源, 2005, 24: 4-7
10李鲜,陈昆松,张明方等.十字花科植物中硫代葡萄糖苷的研究进展[J].园艺学报, 2006, 33: 675-679
1傅婷婷,倪孟祥.核苷类抗艾滋病药物研发近况[J].药学进展,2007, 31: 211-216
2 Kehlenbeck S, Betz U, Birkmann A, et al. Dihydroxythioen- es are novel potent inhibitors of human immunodeficiency virus integrase with a diketo acid-like pharmacophore[J]. Virology, 2006, 80: 6883-6894
3 Johnson A A,Santos W, Pais G C G, et al.Integration requires a specific interaction of the donor DNA terminal 5′-cytosine with glutamine 148 of the HIV-1integrase flexible loop[J]. Biochemistry, 2006, 281: 461-467
4 Diamond T L, Bushman F D.Division of labor within human immunodeficiency virus integrase complexes:Determinant of catalisis and target DNA capture [J]. American Society for Microbiology, 2005, 79: 15376-15387
5 Fesen M R, Kohn K W, Leteurtre F, et al .Inhibitors of human immunodeficiency virus integrase [J]. Pharmacology, 1993, 90: 2399-2403
6 Drake R R, Neamati N, Hong H X, et al. Identification of a nucleotide binding site in HIV-1 integrase [J]. Biochemistry, 1998, 95: 4170-4175
7 Chi G, Neamati N, Nair V. Inhibition of the strand transfer step of HIV 1 integrase by non-natural dinucleotide [J]. Bioorg Med Chem Lett, 2004, 14: 4815-4817
8 Huang S L, Huang P L, Huang P L, et al. Inhibitor of theintegrase of the immunpdeficiency virus(HIV) type by anti- HIV plant proteins MAP30 and GAP31 [J]. Biochemistry, 1995, 92: 8818-8822
9 Gleenberg I O, Avidan O, Goldgur Y, et al. Peptides derived from the reverse transcriptase of human immunodeficiency virus type 1 as novel inhibitors of the viral integrase [J]. Biological chimistry, 2005, 280: 21987–21996
10 Goldgur Y, Craigie R, Cohen G H, et al. Structure of the HIV-1 integrase catalytic domain complexed with an inhibit- or: A platform for antiviral drug design [J]. Biochemistry, 1999, 96: 13040-13043
11 Barreca M L,Lee K W,Chimirri A, et al. Molecular dynamics studies of the wild-type and double mutant HIV-1 integrase complexed with the 5CITEP inhibitor: mechanism for inhibition and drug resistance [J]. Biophysical, 2003, 84: 1450-1463
12 Deprez E, Barbes S, Kolaski M, et al. Mechanism of HIV-1 integrase inhibition by styrylquinoline derivatives in vitro [J]. Molecular pharmacology, 2004, 65: 85-98
13 Ma X H,Zhang X Y,Tan J J,et al.Exploring binding mode for styrylquinoline HIV-1 integrase inhibitors using comparative molecular field analysis and docking studies [J]. Acta pharmacologica sinica, 2004, 25: 950-958
14 Semenova E A,Johonson A A,Marchand C, et al. Preferential inhibition of the magnesium-dependent strand transfer reaction of HIV-1 Integrase byα-Hydroxytropolones [J].Molecular pharmacology, 2006, 69: 1454-1460
15 Kehlenbeck S,Betz U,Birkmann I A,et al. Dihydroxythioph- enes are novel potent inhibitors of human immunodeficiency virus integrase with a diketo acid-like pharmacophore [J]. Virology, 2006, 80: 6883-6894
16 Hazuda D J, Anthony N J,Gomez R P, et al.A naphthyridine carboxamide provides evidence for discordant resistance between mechanistically identical inhibitors of HIV-1 integrase [J]. Biochemistry, 2004, 101:11233-11238
17 Hombrouck A, Hantson A, Remoortel B V, et al. Selection of human immunodeficiency virus type 1 resistance against the pyranodipyrimidine V-165 points to a multimodal mechanism of action [J]. Antimicrobial chemotherapy, 2007, 59: 1084–1095
1 Waszkowycz T D, Perkins R A, Sykes J L. Large-scale virtual screening for discovering leads in the postgenomic era[J]. IBM Systems Journal, 2001, 40: 360-376
2 John T K. Making virtual screening a reality[J]. PNAS, 2003, 100: 6902-6903
3徐筱杰,侯廷军等.计算机辅助药物分子设计[M].北京:化学工业出版社,2004
4郝方,张雪莲,张顺宝等.生物新技术在新药研发中的进展与展望[J].宁夏医学杂志,2005,27:142-143
5 Schellhammer I, Rarey M, Trix X. Structure-based molecule indexing for large-scare virtual screening in sublinear time[J]. Comp.Aided Mol Design, 2007, 21: 223-238
6 Kuntz I D. Structure-based strategies for drug design and discovery[J]. Science, 1992, 257: 1078-1082
7 Diane J, Mc C. Computational approaches to structure-based ligand design[J]. Pharmacology and Therapeutics, 1999, 84: 179-191
8 Bartosz A, Grzybowski, Alexey V, et al. Combinatorial computational methord gives new picomolar ligands for a known enzyme[J]. PNAS, 2002, 99: 1270-1273
9 Martin Y C. 3D database searching in drug design[J]. Med Chem, 1992, 35: 2145-2154
10 Marriott D P, Dougall I G, Meghani P, et al. Lead generation using pharmacophore mapping and three-dimensionaldatabase searching: application to muscarinic M(3) receptor antagonists[J]. Med Chem, 1999, 42: 3210-3216
11 Yasuhisa K. Mesangial cell proliferation inhibitors for the treatment of proliferative glomerular disease[J]. Medicinal Research Reviews, 2002, 23: 15-31
12 Winkler D A, Burden F R. Application of neural networks to large dataset QSAR, virtual screening, and library design[J]. Methods Mol Biol, 2002, 201: 325-367
13范志金,王玲秀,陈俊鹏等.新磺酰脲类除草剂NK#94827的除草活性[J].中国农学通报, 2004, 20: 198-200
14 Beresford A P, Selick H E, Tarbit M H. The emerging importance of predictive ADME simulation in drug discovery[J]. Drug discover today, 2002, 7: 109-116