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; 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）：蛋白质激酶是信号转导网络的关键成分，其故障与疾病有关，包括癌症，炎症，糖尿病和心脏病。传统的药物发现工作已追求针对ATP结合位点的抑制剂，几乎没有考虑蛋白激酶表面上的其他位点。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上的新型小分子结合位点（外s）。我们知道，必须存在其他外神经材料，因为天然产物和合成库的筛选已经确定了许多激酶家族成员的ATP非竞争性抑制剂。这项研究的第一个目标是提供一种新的治疗方法来靶向三种蛋白激酶，蛋白激酶A，蛋白激酶B和Aurora A激酶。这将通过成功完成三个目标（i）来通过计算分析来确定PKA，PKB和Aurora A上的新型可药物位点（“外sosites”）来实现。 （ii）通过虚拟配体筛选鉴定与这些激酶上外os岩结合并抑制功能的小药物样分子； （iii）通过化学优化，结构表征和迭代将这些抑制剂发展为药物铅。在我们的最终目的中：（iv）我们将应用计算分析到整个激酶家族，并确定其他成员的可药物外os虫。我们将通过蛋白质激酶资源（一种基于公共网络的激酶资源）提供我们的发现，以便这些新型外os虫可以由从事特定蛋白质激酶的学术组来瞄准。该项目的性质是多学科的，我们认为，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。