Structure Based design of Meprin A Inhibitors for Acute Nephropathy

描述(申请人提供)：Meprin A是一种低聚锌金属蛋白酶，发现于肾近端小管细胞刷状缘膜上。关于遗传学、meprin活性水平和meprin抑制剂在培养细胞和活体啮齿动物中的作用的各种研究表明，meprin A活性在急性肾功能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米分子的Meprin A小分子抑制剂，作为旨在发现预防和延缓急性肾功能衰竭的临床有用药物的计划的第一步。实验步骤如下：1.检测50个潜在的金属蛋白酶抑制剂对meprin A的抑制作用，并测定其IC50值。2.根据活性数据确定这组抑制剂的构效关系(SAR)。3.使用小鼠meprin A的同源衍生模型，构建假定的人meprin A/抑制剂复合体的三维计算模型。使用Sapient Discovery的蛋白质建模技术，微调该同源模型，以提高预测抑制剂的IC50值的准确性。4.以活性最高的化合物为基础，建立一个包含500个候选抑制剂的虚拟文库，并使用对接程序根据预测的活性对化合物进行排序。5.合成并筛选30个分子，包括这个虚拟文库中最有希望的20个分子。当至少发现一种Meprin A的抑制剂时，第一阶段将成功完成，其IC50=20 NM，分子量小于600道尔顿。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中的有效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，造成超过120亿美元的损失。我们的目标是利用一种创新的基于结构的程序来开发阻断meprin A的候选药物，meprin A是一种在急性肾功能衰竭中发挥关键作用的酶。

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.