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

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。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 布林莫尔学院朱迪思·拉朗德：利用基于ROCS形状的匹配算法开发新型HIV进入抑制剂本计算项目的主要目标是合理地设计小分子拮抗剂，阻断人类CD4细胞表面受体和HIV-1的gp120包膜蛋白之间的相互作用，作为治疗艾滋病的潜在疗法。病毒被膜蛋白gp120在与细胞内的CD4受体结合后会发生很大的构象变化，从而允许随后与趋化因子受体结合以及病毒-宿主细胞融合(1)。NIH PO1 GM 56550项目团队(基于结构的HIV-1包膜功能在细胞进入中的拮抗作用)已经合成并分析了一系列NBD化合物类似物(2)(图1)。这些化合物与CD4与gp120的结合竞争，并增强了CD4：gp120与趋化因子受体CCR5的结合。Schon等人用等温滴定量热法解释了NBD化合物的热力学性质，结果表明该化合物类化合物以类似于CD4结合的方式诱导gp120的结构。这些化合物在与细胞受体结合之前增强和灭活病毒。通过使用Glide(3，4)进行的计算对接研究，预测了这类化合物的结合模式(图1)。对带有关键结合位点残基的一系列NBD化合物的突变分析表明，某些化合物和突变增加了结合亲和力和增强了病毒感染性(7)。这些突变数据提供了导致化合物激动性的关键蛋白质相互作用的信息。在目前的分配过程中，使用了锌集合(8)的800万种类药物化合物的构象数据库和基于ROCs(9-11)形状的虚拟筛选方法。该筛选方案被用于鉴定、合成和测试100多个新的HIV gp120-CD4结合的小分子类似物(12)。其中20多个是有希望进行进一步优化的新类似物。在要求的续展期限内(4-1-11至3-31-12)，ROCS筛选方案将继续用于优化过程。需要在匹兹堡超级计算中心提供90,000个单位的沃霍尔资源，并在更新可用时为软件和PVM支持提供高级技术支持。利用PSC资源进行持续、快速、虚拟的筛查将进一步促进艾滋病毒进入抑制物的发现。

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.