MOLECULAR DYNAMICS STUDIES OF MUTANT HIV GP120 ENVELOP PROTEINS WITH BOUND HIV

这个子项目是许多利用资源的研究子项目之一 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。 Judith LaLonde，Bryn Mawr学院：使用ROCS基于形状的匹配算法开发新型HIV进入抑制剂该计算项目的主要目标是合理设计小分子拮抗剂，其阻断人类CD 4细胞表面受体与HIV-1的gp 120包膜蛋白之间的相互作用，作为治疗艾滋病的潜在疗法。病毒包膜蛋白gp 120在与细胞CD 4受体结合后发生大的构象变化，从而允许随后与趋化因子受体结合和病毒-宿主细胞融合（1）。NIH PO 1 GM 56550项目组（细胞进入中HIV-1包膜功能的基于结构的拮抗作用）合成并测定了一系列NBD化合物类似物（2）（图1）。这些化合物与CD 4竞争结合gp 120，并增强CD 4：gp 120与趋化因子受体CCR 5的结合。Schon等人（2）通过等温滴定量热法对NBD化合物的热力学性质进行了阐明，表明该化合物类以类似于CD 4结合的方式诱导gp 120的结构化。这些化合物在与细胞受体结合之前增强并灭活病毒。使用Glide（3，4）进行的计算对接研究产生了这类化合物的预测结合模式（图1）。具有关键结合位点残基的NBD化合物系列的突变分析显示，某些化合物和突变增加了结合亲和力并增强了病毒感染性（7）。该突变数据提供了负责化合物激动性质的关键蛋白质相互作用的信息。在当前分配过程中，使用800万种药物样化合物的锌集合（8）的构象异构体数据库与基于ROCS（9-11）形状的虚拟筛选方法。该筛选方案用于鉴定、合成和测试超过100种新的HIV gp 120-CD 4结合的小分子类似物（12）。其中有二十多个是有前途的新的类似物，进一步优化。ROCS筛选方案将在申请的更新期（2011年4月1日至2012年3月31日）内继续用于优化过程。在匹兹堡超级计算中心的沃霍尔上有90,000 SU的资源，以及在更新可用时对软件和PVM支持的高级技术支持。使用PSC资源进行持续、快速、虚拟筛选将进一步促进HIV进入抑制剂的发现。

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. Judith LaLonde, Bryn Mawr College: Development of Novel HIV Entry Inhibitors Using the ROCS Shaped Based Matching Algorithm The key objective of this computational project is to rationally design small-molecule antagonists that block the interaction between the human CD4 cell-surface receptor and the gp120 envelop protein of HIV-1 as potential therapeutics for the treatment of AIDS. The viral envelop protein, gp120, undergoes a large conformational change upon binding to the cellular CD4 receptor allowing subsequent binding to the chemokine receptor and viral-host cell fusion (1). The NIH PO1 GM 56550 project team (Structure-Based Antagonism of HIV-1 Envelope Function in Cell Entry) has synthesized and assayed a series of NBD compound analogs (2) (Figure 1). These compounds compete with CD4 binding to gp120 and enhance binding of CD4:gp120 to the chemokine receptor CCR5. Elucidation of the thermodynamic properties of NBD compounds via isothermal titration calorimetry by Schon et al (2) indicates that this compound class induces the structuring of gp120 in a manner similar to CD4 binding. These compounds enhance and inactive the virus prior to binding to the cellular receptor. A predicted binding mode for this class of compounds has been produced from computational docking studies using Glide (3, 4), (Figure 1). Mutational analysis of the series of NBD compounds with key binding site residues has shown certain compounds and mutations increase binding affinity and enhance viral infectivity (7). This mutational data provides information of key protein interactions responsible for the agonistic properties of the compounds. Over the course of the current allocation the conformer data base of the Zinc collection (8) of 8 million drug-like compounds was used with ROCS (9-11) shaped-based virtual screening methods. This screening protocol was used to identify, synthesize and test over 100 new small molecule analogues of HIV gp120-CD4 binding (12). Over twenty of these are promising new analogues for further optimization. The ROCS screening protocol will continue to be used in the optimization process under the requested renewal period (4-1-11 to 3-31-12). A resource of 90,000 SU on Warhol at the Pittsburgh Super Computing Center as well as Advanced Technical Support for software and PVM support when updates are available is requested. Continued, rapid, virtual screening using PSC resources will further promote the discovery of HIV entry inhibitors.