COMPUTATIONAL APPROACHES TO UNDERSTAND THE INTERACTION OF HIV-1 INTEGRASE AND I

理解 HIV-1 整合酶和 I 相互作用的计算方法

• 批准号: 8364198
• 负责人: Zengjian Hu
• 金额: $ 0.2万
• 依托单位: CARNEGIE-MELLON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8364198
• 关键词: AIDS therapy; Anti-HIV Agents; Binding; Biological Factors; Biomedical Research; Catalytic Domain; Cells; Chinese Herbs; Chromosomes; Complement; Complex; DNA; Drug Design; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Enzymes; Exhibits; Funding; Genome; Grant; HIV; HIV Protease; HIV-1; Herbal Medicine; High Performance Computing; Integrase; Lead; Life Cycle Stages; Methodology; Molecular Models; National Center for Research Resources; Principal Investigator; Research; Research Infrastructure; Resources; Reverse Transcriptase Inhibitors; Scutellaria baicalensis; Source; Structure; Techniques; Therapeutic Uses; United States National Institutes of Health; Work; baicalein; baicalin; base; cost; design; drug candidate; inhibitor/antagonist; molecular modeling

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. An essential step in the life cycle of human immunodeficiency virus type 1 (HIV-1) is integration of the double-stranded retroviral DNA into the genome of the host cell. HIV-1 integrase, the enzyme that insertors, ts the vital DNA into the host chromosome, is an attractive and rational target for anti-AIDS drug design because it is essential for HIV replication and there are no known counterparts in the host cell. Inhibitors of this enzyme have the great potential to complement the therapeutic use of HIV protease and reverse transcriptase inhibitors. Natural products have provided a source of new drug candidates for anti-AIDS therapy. The number of compounds exhibiting anti-HIV activity and isolated from natural sources has increase steadily. Baicalein and baicalin, identified components of a Chinese herbal medicine Scutellaria baicalensis Georgi, have been shown to inhibit infectivity and replication of HIV. They are therefore promising lead compounds for developing new anti-AIDS drugs. To understand how the inhibitors work and therefore design more potent and specific inhibitors, we have used molecular modeling techniques to investigate the binding modes of these inhibitors. Computational binding studies of these inhibitors, based on the crystal structure of the HIV-1 integrase catalytic domain, will be performed to study the complex structure using QM/MM methodology.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的主要研究者可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 1 型人类免疫缺陷病毒 (HIV-1) 生命周期中的一个重要步骤是将双链逆转录病毒 DNA 整合到宿主细胞的基因组中。 HIV-1整合酶是将重要DNA插入宿主染色体的酶，是抗艾滋病药物设计的一个有吸引力且合理的靶标，因为它对于HIV复制至关重要，并且宿主细胞中没有已知的对应物。这种酶的抑制剂具有补充 HIV 蛋白酶和逆转录酶抑制剂的治疗用途的巨大潜力。天然产物为抗艾滋病治疗提供了新的候选药物来源。从天然来源中分离出的具有抗 HIV 活性的化合物数量稳步增加。黄芩素和黄芩苷是中草药黄芩中的成分，已被证明可以抑制艾滋病毒的感染和复制。因此，它们是有前途的用于开发新的抗艾滋病药物的先导化合物。为了了解抑制剂的工作原理并设计更有效和特异性更强的抑制剂，我们使用分子建模技术来研究这些抑制剂的结合模式。将基于 HIV-1 整合酶催化结构域的晶体结构对这些抑制剂进行计算结合研究，以使用 QM/MM 方法研究复杂结构。