"Protein protein interaction directed libraries"

“蛋白质蛋白质相互作用定向文库”

• 批准号: 8136604
• 负责人: BILLY W DAY
• 金额: $ 37.82万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8136604
• 关键词: Address; Alzheimer' s Disease; Amino Acids; Applications Grants; Biological; Complement; Diabetes Mellitus; Disease; Future; Hot Spot; Lead; Libraries; Malignant Neoplasms; Medical; Pathway interactions; Pattern; Pharmaceutical Preparations; Probability; Proteins; Screening procedure; Site; base; design; high throughput screening; novel; phenylalanylleucine; phenylalanyltryptophan; protein protein interaction; public health relevance; scaffold; small molecule libraries; success

DESCRIPTION (provided by applicant): The P41 grant proposal (Pilot-Scale Libraries (PSL) for High-Throughput Screening) titled "Protein protein interaction directed compound libraries" will produce 1,760 compounds based on 56 scaffolds aiming to (ant-) agonize protein protein interaction (PPI). It is well established that PPI interfaces - although not easily to categorize - do not have random amino acid distribution. In fact many PPIs have a higher than average Phe, Trp and Leu content and these are the most abundant amino acids in the center of PPI interfaces. These anchor residues are often deeply hurried in the interfaces and contribute much of the energy of interaction of the two proteins. Those energetically important sites are often called "hot-spot". Based on our in depth analysis of many PPI Interfaces containing Trp, Phe and Leu we herein propose that small molecule libraries containing Trp,Phe and Leu fragments should have a much larger probability to (ant-)agonize PPIs than usual screening libraries. This is also based on our recent success of finding very potent antagonists for the cancer relevant PPI p53/mdm2 and p53/mdm4 where we used Trp as a central anchor fragment in the design of antagonists. The herein synthesized compounds will complement current screening libraries of the MLSMR by likely targeting protein protein interactions. Protein interactions are involved in all disease relevant pathways and are of uttermost importance to understand for the future design of novel drugs to address unmet medical needs, such as diabetes, cancer and Alzheimer's disease. PUBLIC HEALTH RELEVANCE: The proposal addresses the RFA by providing compounds which are designed to (ant-)agonize protein protein interaction. The libraries most likely will result in novel biological patterns and lead to further follow on projects aiming to deconvolute their mode-of-actions. The compounds are of high analytical quality, novel, diverse and biologically inspired.

描述（由申请人提供）：题为“蛋白质相互作用定向化合物库”的 P41 拨款提案（用于高通量筛选的中试规模库（PSL））将基于 56 个支架产生 1,760 种化合物，旨在（抗）激动蛋白质蛋白质相互作用（PPI）。 众所周知，PPI 界面（虽然不容易分类）不具有随机氨基酸分布。事实上，许多 PPI 的 Phe、Trp 和 Leu 含量高于平均水平，这些是 PPI 界面中心最丰富的氨基酸。这些锚定残基通常深深地固定在界面中，并贡献两种蛋白质相互作用的大部分能量。这些能量上重要的站点通常被称为“热点”。基于我们对许多含有 Trp、Phe 和 Leu 的 PPI 界面的深入分析，我们在此提出，含有 Trp、Phe 和 Leu 片段的小分子文库应该比通常的筛选文库具有更大的（抗）激动 PPI 的概率。这也是基于我们最近成功找到了癌症相关 PPI p53/mdm2 和 p53/mdm4 的非常有效的拮抗剂，其中我们在拮抗剂的设计中使用 Trp 作为中心锚定片段。本文合成的化合物将通过可能的靶向蛋白质相互作用来补充MLSMR的当前筛选文库。蛋白质相互作用涉及所有疾病相关途径，对于了解未来设计新药以满足未满足的医疗需求（例如糖尿病、癌症和阿尔茨海默病）至关重要。 公共健康相关性：该提案通过提供旨在（抗）激动蛋白质相互作用的化合物来解决 RFA 问题。这些库很可能会产生新的生物模式，并导致进一步跟进旨在解开其作用模式的项目。这些化合物具有高分析质量、新颖、多样且受生物学启发。