Novel Druggable Exosites in Protein Kinases

蛋白激酶中新型可药物外泌体

• 批准号: 7094359
• 负责人: RUBEN ABAGYAN
• 金额: $ 35.79万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7094359
• 关键词: X ray crystallography; allosteric site; computational biology; drug discovery /isolation; drug screening /evaluation; enzyme inhibitors; gel electrophoresis; ligands; nanotechnology; peptide chemical synthesis; pharmacokinetics; protein kinase A; protein structure function; serine threonine protein kinase; small molecule; surface plasmon resonance; tissue /cell culture

DESCRIPTION (provided by applicant): Protein Kinases are critical constituents of signal transduction networks and their malfunction is associated with disease including cancer, inflammation, diabetes, and heart disease. Traditional drug discovery efforts have pursued inhibitors that target the ATP binding site with little consideration for other sites on protein kinase surfaces. Our hypothesis is that we can use structure-based design techniques to identify novel small molecule binding sites (exosites) on the surface of protein kinases. We know that other exosites must exist because screens of natural products and synthetic libraries have identified ATP-noncompetitive inhibitors for many members of the kinase family. The first goal of this research is to provide a new therapeutic approach to target three protein kinases, Protein Kinase A, Protein Kinase B and Aurora A Kinase. This will be achieved by the successful completion of three aims (I) To identify, through computational analysis, novel druggable sites ('exosites') on PKA, PKB and Aurora A; (II) To identify, by virtual ligand screening, small drug-like molecules that bind to exosites on these kinases and inhibit function; (III) To develop these inhibitors into drug-leads through chemical optimization, structural characterization and iteration. In our final aim: (IV) We will apply our computational analysis to the whole kinase family and identify druggable exosites for other members. We will make available our findings through the Protein Kinase Resource (a public web-based kinase resource), so that these novel exosites can be targeted by academic groups working on specific protein kinases. The nature of the project is multi-disciplinary and we believe that the goals are within reach due to our combined expertise in computational, molecular and structural biology.

描述（由申请人提供）：蛋白激酶是信号转导网络的关键组成部分，其功能障碍与癌症、炎症、糖尿病和心脏病等疾病相关。传统的药物发现工作一直在寻找靶向 ATP 结合位点的抑制剂，而很少考虑蛋白激酶表面的其他位点。我们的假设是，我们可以使用基于结构的设计技术来识别蛋白激酶表面的新型小分子结合位点（外部位点）。我们知道一定存在其他外部位点，因为天然产物和合成文库的筛选已经鉴定出激酶家族许多成员的 ATP 非竞争性抑制剂。这项研究的首要目标是提供一种针对三种蛋白激酶（蛋白激酶 A、蛋白激酶 B 和极光 A 激酶）的新治疗方法。这将通过成功完成三个目标来实现 (I) 通过计算分析识别 PKA、PKB 和 Aurora A 上的新型可成药位点（“exosites”）； (II) 通过虚拟配体筛选，鉴定与这些激酶上的外部位点结合并抑制功能的药物样小分子； (III) 通过化学优化、结构表征和迭代将这些抑制剂开发成先导药物。我们的最终目标是：（IV）我们将把我们的计算分析应用于整个激酶家族，并为其他成员识别可药物化的外部位点。我们将通过蛋白激酶资源（基于公共网络的激酶资源）提供我们的发现，以便研究特定蛋白激酶的学术团体可以针对这些新颖的外来位点。该项目的性质是多学科的，我们相信，由于我们在计算、分子和结构生物学方面的综合专业知识，目标是可以实现的。