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

趋化因子受体和其他 GPCR 结构-活性建模工具

• 批准号: 7935070
• 负责人: Benjamin Jacob Doranz
• 金额: $ 17.18万
• 依托单位: INTEGRAL MOLECULAR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7935070
• 关键词: Abbreviations; Address; Adrenergic Receptor; Amino Acids; Antibodies; Binding; Biological; Biological Assay; CCR1 gene; CCR5 gene; CXCR3 gene; CXCR4 gene; Cells; Characteristics; Complex; Computer Simulation; Computer software; Data; Docking; Drug Delivery Systems; Drug Industry; Family; Fee-for-Service Plans; G-Protein-Coupled Receptors; Generations; Goals; HIV-1; Health; Human; Individual; Knowledge; Libraries; Ligands; Maps; Metric; Mining; Modeling; Molecular; Molecular Structure; Monoclonal Antibodies; Mutate; Performance; Pharmaceutical Preparations; Phase; Production; Proteins; Protocols documentation; Publishing; Quality Control; RANTES; Resolution; Sales; Side; Software Tools; Structure; Structure-Activity Relationship; Supporting Cell; Testing; Validation; base; cDNA Arrays; chemokine; chemokine receptor; comparative; data management; design; drug candidate; drug development; meetings; mutant; pathogen; prototype; receptor; small molecule; three-dimensional modeling; tool

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.

描述（由申请人提供）：了解药物及其靶标之间的精确分子相互作用，其结构活性关系（SAR）是药物开发期间的非常理想的目标。 GPCR是制药行业中最大的药物靶标系列，但有关它们的结构信息非常困难。该提案将产生的产物，结构活性关系阵列（Sarray）将使GPCR与药物候选物和其他配体的结构相互作用在分子分辨率下确定。我们已经证明了构建sarrays并使用它们来获得有用的结构信息的可行性。我们确定了五种不同CCR5分子相互作用的结构决定因素，包括负责与趋化因子（RANTES）相互作用的关键氨基酸，两种单克隆抗体（2D7和45523），HIV-1 ENV（JRFL）和一种小分子药物（TAK-7779）。我们的结果得到了验证，并同意已发表的结果。我们2阶段建议的具体目的是：I。测试Sarray数据预测详细的受体 - 配体相互作用II的能力II。开发结构活性分析工具和数据管理软件。 iii。为经过验证的GPCR药物目标创建SARRAYS，该产品由该提案产生的产品将通过促进针对GPCR的药物的优化和设计来促进人类健康。了解药物及其靶标之间的确切分子相互作用，它们的结构活性关系（SAR）是药物开发期间非常理想的目标。 GPCR是制药行业中最大的药物靶标系列，但有关它们的结构信息非常困难。

项目成果

Atomic-level mapping of antibody epitopes on a GPCR.

• DOI: 10.1021/ja900186n
• 发表时间: 2009-05-27
• 期刊: Journal of the American Chemical Society
• 影响因子: 15
• 作者: Paes C;Ingalls J;Kampani K;Sulli C;Kakkar E;Murray M;Kotelnikov V;Greene TA;Rucker JB;Doranz BJ
• 通讯作者: Doranz BJ