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

这个子项目是利用资源的许多研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 人类免疫缺陷病毒1型（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整合酶是一种将重要DNA插入宿主染色体的酶，由于其对HIV复制至关重要，并且在宿主细胞中没有已知的对应物，因此它是抗艾滋病药物设计的一个有吸引力和合理的靶标。这种酶的抑制剂有很大的潜力，以补充艾滋病毒蛋白酶和逆转录酶抑制剂的治疗用途。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活性的化合物的数量稳步增加。黄芩素和黄芩苷是中草药黄芩的鉴定成分，已显示出抑制HIV的感染性和复制。因此，它们是开发新的抗艾滋病药物的有希望的先导化合物。为了了解抑制剂如何工作，从而设计更有效和更特异的抑制剂，我们使用分子模拟技术来研究这些抑制剂的结合模式。基于HIV-1整合酶催化结构域的晶体结构，将对这些抑制剂进行计算结合研究，以使用QM/MM方法研究复合物结构。

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.