Insight and Optimization of Metalloprotein Inhibitors

 描述(由申请人提供)：这个持续的项目专注于为发现金属蛋白抑制剂开发新的途径、方法和战略。金属蛋白是一类重要的药物靶点，与治疗多种疾病有关，包括但不限于癌症、关节炎和细菌感染。大多数抑制金属蛋白的治疗药物使用金属结合的药效团(MBP)来结合活性部位的金属离子。尽管这些Mbps很重要，但很少有研究集中于识别、优化和了解什么Mbps对特定目标金属蛋白靶标最好的方法。在上一次研究期间(2011年9月至2014年7月，本更新提交时约34个月)，该计划产生了几项与金属蛋白抑制剂相关的新发现，包括：a)针对几种金属蛋白靶标筛选MBP等压力库，并开发HIT化合物的子库；b)获得典型金属蛋白(碳酸酐酶)中MBP的热力学和结构数据；c)使用计算方法对这些相互作用进行建模，以了解我们发现的分子基础；以及d)评估几种金属蛋白抑制剂的靶标选择性。之前的项目期间非常富有成效，产生了大约15份手稿，一个书籍章节，几项专利披露，并为一家生物技术初创公司的形成做出了贡献。在正在进行的研究中，我们建议大大扩大我们目前的努力，以及探索与发现、开发和优化金属蛋白抑制剂相关的其他研究领域。在具体目标1中，我们将开发合理的新的MBP文库 针对特定类别的金属蛋白(例如，具有包含两个相邻金属离子的双核活性中心的金属蛋白)。在具体目标2中，我们将进一步努力研究MBP结合的结构生物学和计算模型，包括研究金属离子活性中心组成的变化如何改变MBP亲和力。在具体目标3中，我们将研究金属蛋白抑制剂对其靶标酶的选择性。我们将评估金属蛋白抑制剂在竞争金属蛋白存在的情况下的活性，并研究金属酶抑制剂处理如何扰乱活细胞中金属离子的动态平衡。最后，我们将继续帮助世界各地的研究人员，根据新的金属蛋白靶标筛选我们的文库，并开发子文库，从点击到领先完成这些努力。

 DESCRIPTION (provided by applicant): This continuing project is focused on developing new approaches, methods, and strategies for the discovery of metalloprotein inhibitors. Metalloproteins are an important class of medicinal targets that are relevant to treating numerous diseases including but not limited to cancer, arthritis, and bacterial infections. Most therapeutics that inhibit metalloproteins employ a metal-binding pharmacophore (MBP) to bind to the active site metal ion. Despite the importance of these MBPs, few studies have focused on methods to identify, optimize, and understand what MBPs are best for a given metalloprotein target of interest. In the last research period (9/2011 - 7/2014, ~34 months at the time of this renewal submission), this program generated several new findings relevant to metalloprotein inhibitors, including: a) screening of an MBP isostere library against several metalloproteins targets and developing sub libraries of hit compounds; b) obtaining thermodynamic and structural data on MBPs in an archetypal metalloprotein (carbonic anhydrase); c) modeling of these interactions using computational approaches in order to understand the molecular basis for our findings; and d) assessing the on-target selectivity of several metalloprotein inhibitors. The previous project period was very productive, yielding ~15 manuscripts, one book chapter, several patent disclosures, and contributing to the formation of a biotechnology startup company. In ongoing studies, we propose to greatly expand our current efforts, as well as explore other areas of investigation relevant to the discovery, development, and optimization of metalloprotein inhibitors. In Specific Aim 1, we will develop new MBP libraries that are rationally tailored toward certain classes of metalloproteins (e.g. those with dinuclear active sites containing two adjacent metal ions). In Specific Aim 2, we will expand our efforts on the structural biology and computational modeling of MBP binding, including an examination of how changes in metal ion active site composition alter MBP affinity. In Specific Aim 3, we will study the selectivity of metalloprotein inhibitors for their target enzymes. We will evaluate the activit of metalloprotein inhibitors in the presence of competing metalloproteins and investigate how treatment with metalloenzyme inhibitors perturbs metal ion homeostasis in living cells. Finally, we will continue to aid investigators around the world by screening our libraries against new metalloprotein targets and by developing sub libraries that take these efforts from hit-to-lead.