Structure-based, Rational Design of RhoGEF, GGTase I and RhoKinase Inhibitors

基于结构的 RhoGEF、GGTase I 和 RhoKinase 抑制剂的合理设计

• 批准号: 7882864
• 负责人: Nicolas Lawrence
• 金额: $ 30.93万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7882864
• 关键词: Biological Availability; Biological Process; Cardiovascular system; Diabetes Mellitus; Disadvantaged; Disease; Face; HIV; Hydrogen Bonding; Malignant Neoplasms; Mediating; Neurodegenerative Disorders; Peptides; Play; Positioning Attribute; Protein-Serine-Threonine Kinases; Proteins; Reporting; Rho-associated kinase; Role; Secondary Protein Structure; Solubility; Structure; Surface; Therapeutic; Water; base; design; improved; inhibitor/antagonist; innovation; mimetics; mimicry; novel; protein geranylgeranyltransferase; protein protein interaction; rho; scaffold; small molecule

Protein-protein Interactions (PPIs) play critical roles in biological processes that can propagate or terminate llfe.These PPIs have been Implicated In numerous disease states, including HIV, diabetes, and cardiovascular and neurodegenerative diseases, making them Important targets for dIsruptlon.Often recognition between proteins is mediated by protein secondary structures, such as a-helices, via one helical face, where interacting residues occupy predominantly the /, / + 3 or / + 4, and / + 7 positions. Accordingly, these surfaces are critical targets for small molecule mimicry. Our previous focus has yielded a-helix mimetics with Inherent disadvantages, either poor solubility (terphenyl and terpyridine scaffolds) or hydrogen-bonding networks to maintain their correct orientation (terephthalamide and thspyrldylamlde scaffolds). As a mechanism to overcome the disadvantages of our previous designs, we have reported an Innovative scaffold that replaces the terminal six-membered aromatic end units with water-soluble five-membered heterocyclic groups.

蛋白质-蛋白质相互作用（PPIs）在生物过程中起着关键作用，可以繁殖或终止生命。这些PPIs与许多疾病状态有关，包括HIV、糖尿病、心血管和神经退行性疾病，使它们成为dIsruptlon的重要靶点。蛋白质之间的识别通常由蛋白质二级结构介导，如a-螺旋，通过一个螺旋面，其中相互作用残基主要占据/，/ + 3或/ + 4和/ + 7位置。因此，这些表面是小分子模拟的关键目标。我们之前的研究重点是产生具有固有缺点的a-螺旋模拟物，要么溶解度差（terphenyl和terpyridine支架），要么氢键网络保持其正确的取向（terephthalamide和thspyryllamlde支架）。作为一种克服我们以前设计的缺点的机制，我们报告了一种创新的支架，它取代了