A Tool for Modeling the Structure-Activity of Chemokine Receptors and Other GPCRs

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。GPCR是制药业中单一的最大的药物靶标家族，但关于它们的结构信息非常难以获得。根据这一提议产生的产品，结构-活性关系阵列(SARray)，将使GPCRs与候选药物和其他配体的结构相互作用能够在分子分辨率下确定。我们已经证明了构建SARray和使用它们来获取有用的结构信息的可行性。我们确定了五个不同CCR5分子相互作用的结构决定因素，包括与趋化因子(RANTES)、两个单抗(2D7和45523)、HIV-1Env(JRFL)和小分子药物(TAK-779)相互作用的关键氨基酸。我们的结果与已发表的结果进行了验证，并与已发表的结果一致。我们第二阶段计划的具体目标是：1.测试SARray数据预测详细受体-配体相互作用的能力；2.开发结构-活性分析工具和数据管理软件。创建针对GPCRs有效药物靶点的SARray本提案所产生的产品将通过促进针对GPCRs的药物的优化和设计而对人类健康作出贡献。了解药物与其靶标之间的精确分子相互作用，即其构效关系(SAR)，是药物开发过程中非常理想的目标。GPCR是制药业中单一的最大的药物靶标家族，但关于它们的结构信息非常难以获得。

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. GPCRs are the single largest family of drug targets in the pharmaceutical industry, yet structural information about them is exceptionally difficult to obtain. The product that will arise from this proposal, the Structure-Activity Relationship Array (SARray), will enable structural interactions of GPCRs with drug candidates and other ligands to be determined at molecular resolution. We have demonstrated the feasibility of constructing SARrays and of using them to obtain useful structural information. We identified the structural determinants of five different CCR5 molecular interactions, including critical amino acids responsible for interacting with a chemokine (RANTES), two monoclonal antibodies (2D7 and 45523), HIV-1 Env (JRFL), and a small- molecule drug (TAK-779). Our results were validated against and agree with published results. The Specific Aims of our Phase 2 proposal are: I. Test the ability of SARray data to predict detailed receptor-ligand interactions II. Develop structure-activity analysis tools and data management software. III. Create SARrays for validated GPCR drug targets The product that results from this proposal will contribute to human health by facilitating the optimization and design of drugs targeted to GPCRs. Understanding the precise molecular interactions between drugs and their targets, their structure-activity relationship (SAR), is a highly desirable goal during drug development. GPCRs are the single largest family of drug targets in the pharmaceutical industry, yet structural information about them is exceptionally difficult to obtain.