Structure Based design of Meprin A Inhibitors for Acute Nephropathy

基于结构的急性肾病 Meprin A 抑制剂的设计

• 批准号: 7327013
• 负责人: Kal Ramnarayan
• 金额: $ 10.7万
• 依托单位: SAPIENT DISCOVERY, LLC
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-07 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7327013
• 关键词: 3-Dimensional; Acute; Acute Kidney Failure; Affect; American; Apoptosis; Binding; Biological Assay; Cells; Cessation of life; Complex; Computer Simulation; Cultured Cells; Data; Death Rate; Disease; Docking; End stage renal failure; Enzymes; Epithelial; Etiology; Free Energy; Genetic; Genetic Engineering; Goals; Grant; Homology Modeling; Human; Inhibitory Concentration 50; Interstitial Collagenase; Kidney; Kidney Diseases; Libraries; Life; Meprin; Metalloproteases; Modeling; Molecular Weight; Mus; Pharmaceutical Preparations; Phase; Physiological reperfusion; Plasma; Play; Prevention; Procedures; Property; Proteins; Proximal Kidney Tubules; Rattus; Reperfusion Therapy; Rodent; Role; Screening procedure; Structure; Structure-Activity Relationship; Synthesis Chemistry; Technology; Treatment Cost; United States; Virtual Library; X-Ray Crystallography; Zinc; astacin; base; brush border membrane; cost; dalton; design; experience; improved; inhibitor/antagonist; innovation; meprin A; metalloenzyme; novel; programs; renal ischemia; small molecule; three dimensional structure

DESCRIPTION (provided by applicant): Meprin A is an oligomeric zinc metalloproteinase found at the brush border membranes of kidney proximal tubule cells. A variety of studies involving genetics, meprin activity levels, and meprin inhibitor effects in cultured cells and live rodents suggest that meprin A activity plays a key role in the etiology of acute kidney failure. This deadly disease affects over 250,000 Americans each year, with a 60% death rate. The treatment costs for end-stage renal disease are over $12 billion annually in the United States alone. We propose to design and synthesize low nanomolar, small molecule inhibitors of meprin A as the first step in a program aimed at discovering clinically useful agents for the prevention and delay of acute kidney failure. The steps involved are as follows: 1. Assay 50 potential metalloprotease inhibitors with relevant structures for their ability inhibit meprin A and determine the IC50 values. 2. Based on the activity data determine the structure activity relationship (SAR) for this set of inhibitors. 3. Construct 3- dimensional computational models for putative human meprin A/inhibitor complexes by using a homology-derived model of murine meprin A. Using the protein modeling technology at Sapient Discovery, fine-tune this homology model to improve the accuracy of prediction of the IC50 values for the inhibitors. 4. Based on the most active compounds develop a focused virtual library of 500 inhibitor candidates and use docking procedures to rank order the compounds based on predicted activity. 5. Synthesize and screen 30 molecules, including 20 of the most promising molecules in this virtual library. Phase I will be successfully completed when at least one inhibitor of meprin A is discovered with IC50 = 20 nM and a molecular weight of less than 600 Daltons. The considerable experience in the rational design, synthesis and screening of metalloproteinase inhibitors at Sapient Discovery will be directly applicable to the proposed discovery of potent meprin A inhibitors. Each year, acute kidney failure affects more than 250,000 Americans, causing over 150,000 deaths at a cost exceeding 12 billion dollars. We aim to develop drug candidates that block meprin A, an enzyme that plays a key role in acute kidney failure using an innovative structure-based procedure.

描述（由申请方提供）：Meprin A是一种在肾近端小管细胞刷状缘膜发现的寡聚锌金属蛋白酶。涉及遗传学、meprin活性水平和meprin抑制剂在培养细胞和活啮齿动物中的作用的各种研究表明，meprin A活性在急性肾衰竭的病因学中起关键作用。这种致命的疾病每年影响超过25万美国人，死亡率为60%。仅在美国，终末期肾病的治疗费用每年就超过120亿美元。我们建议设计和合成低纳摩尔，小分子抑制剂的meprin A的第一步，旨在发现临床上有用的药物，用于预防和延迟急性肾功能衰竭的计划。所涉及的步骤如下：1.测定50种具有相关结构的潜在金属蛋白酶抑制剂抑制meprin A的能力，并测定IC 50值。2.基于活性数据确定这组抑制剂的结构活性关系（SAR）。3.通过使用小鼠meprin A的同源衍生模型，构建推定的人meprin A/抑制剂复合物的三维计算模型。使用Sapient Discovery的蛋白质建模技术，微调该同源性模型，以提高抑制剂IC 50值预测的准确性。4.基于最具活性的化合物，开发一个包含500种候选抑制剂的集中虚拟库，并使用对接程序根据预测的活性对化合物进行排序。5.合成和筛选30个分子，包括这个虚拟库中最有前途的20个分子。当发现至少一种Meprin A抑制剂的IC 50 = 20 nM且分子量小于600道尔顿时，I期将成功完成。Sapient Discovery在金属蛋白酶抑制剂的合理设计、合成和筛选方面的丰富经验将直接适用于拟议的强效meprin A抑制剂的发现。每年，急性肾衰竭影响超过25万美国人，造成超过15万人死亡，花费超过120亿美元。我们的目标是开发阻断meprin A的候选药物，meprin A是一种使用创新的基于结构的程序在急性肾衰竭中发挥关键作用的酶。