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.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。 列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 人类免疫缺陷病毒1型（HIV-1）生命周期中的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积分酶是插入，将重要DNA插入宿主染色体中的酶，是抗AIDS药物设计的有吸引力且合理的靶标，因为它对于HIV复制至关重要，并且在宿主细胞中没有已知的对应物。该酶的抑制剂具有补充HIV蛋白酶和逆转录酶抑制剂的治疗使用的巨大潜力。天然产品为抗AID疗法提供了新的候选药物来源。表现出抗HIV活性和从天然来源分离的化合物的数量稳定增加。贝拉西林和黄氨酸菌鉴定出了中草药scutellaria baicalensis georgi的成分，已显示出抑制HIV的感染性和复制性。因此，它们是开发新抗AIDS药物的有希望的铅化合物。为了了解抑制剂的工作方式，因此设计了更有效和特定的抑制剂，我们使用了分子建模技术来研究这些抑制剂的结合模式。这些抑制剂的计算结合研究将基于HIV-1整合酶催化结构域的晶体结构，使用QM/MM方法研究复杂结构。