Modeling the Structure-Activity of Chemokine Receptors

描述(由申请人提供)：在药物开发过程中，了解药物与其靶标之间的精确分子相互作用及其构效关系(SAR)是一个非常理想的目标。阐明G蛋白偶联受体(GPCRs)的SAR是一项复杂的任务，因为这些蛋白质的直接结构可视化是困难或不可能的。我们已经创建了一种名为结构-活性关系阵列(SARray)的产品，可以在氨基酸侧链相互作用的详细水平上确定候选药物与GPCRs的结构和功能相互作用。这项提案的主要目标是创建一种工具，促进GPCRs的药物优化。在第一阶段开发和测试的SARray原型将专注于趋化因子受体CCR5。所有20种趋化因子受体的SARray将在第二阶段开发，任何膜蛋白的定制SARray将在第三阶段提供。这些阵列(我们的实体产品)将与阵列分析和处理的协议和支持一起发送给客户。在初步实验中，我们创建了一个CCR5 SARray原型。SARray被快速检测为五种不同的功能，包括评估抗体结合表位和HIV-1辅助受体功能。即使在我们的小规模文库中也发现了相关的分子相互作用，这表明我们的GPCRs的SAR分析策略是可以实现的。我们第一阶段提案的具体目标是：具体目标I。创建一个全面的SARray，其中可以分析GPCR中每一种氨基酸的功能作用。特定目的II.分析GPCRs的构效关系。

DESCRIPTION (provided by applicant): Understanding the precise molecular interactions between drugs and their targets, their structure-activity relationship (SAR), is a highly desirable goal during drug development. Elucidation of SAR for G protein-coupled receptors (GPCRs) is a complicated task because direct structural visualization of these proteins is difficult or impossible. We have created a product, the Structure-Activity Relationship Array (SARray), that enables structural and functional interactions of drug candidates with GPCRs to be determined at the detailed level of amino acid side-chain interactions. The primary goal of this proposal is to create a tool that will facilitate drug optimization for GPCRs. The prototype SARray, developed and tested in Phase 1, will focus on the chemokine receptor CCR5. SARrays for all twenty chemokine receptors will be developed in Phase 2, and customized SARrays for any membrane protein will be offered in Phase 3. These arrays (our physical product) will be sent to customers with protocols and support for array analysis and processing. In preliminary experiments, we created a prototype CCR5 SARray. The SARray was rapidly assayed for five different functions, including evaluation of antibody binding epitopes and HIV-1 coreceptor function. Relevant molecular interactions were identified, even within our small-scale library, suggesting that our strategy for SAR analysis of GPCRs can be accomplished. The Specific Aims of our Phase I proposal are: Specific Aim I. Create a Comprehensive SARray in which the Functional Role of Every Amino Acid of a GPCR can be Assayed. Specific Aim II. Analyze Structure-Activity Relationships of a GPCR.