Insight and Optimization of Metalloprotein Inhibitors

 描述（由申请人提供）：该持续项目的重点是开发新的途径，方法和策略，用于发现金属蛋白抑制剂。金属蛋白是一类重要的药物靶标，其与治疗许多疾病相关，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剂采用金属结合药效团（MBP）来结合活性位点金属离子。尽管这些MBPs的重要性，很少有研究集中在方法来识别，优化，并了解什么MBPs是最好的一个给定的金属蛋白目标的兴趣。 在上一个研究阶段，（2011年9月至2014年7月，本次更新提交时约34个月），该项目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等排体文库并开发命中化合物的子文库; B）获得原型金属蛋白中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，以便理解我们发现的分子基础;和d）评估几种金属蛋白抑制剂的靶向选择性。上一个项目期间非常富有成效，产生了约15份手稿，一本书的章节，几项专利披露，并促成了一家生物技术创业公司的成立。 在正在进行的研究中，我们建议大大扩大我们目前的努力，以及探索与金属蛋白抑制剂的发现，开发和优化相关的其他研究领域。在具体目标1中，我们将开发新的MBP库， 针对某些类别的金属蛋白（例如，具有含有两个相邻金属离子的双核活性位点的那些）定制。在具体目标2中，我们将扩大我们对MBP结合的结构生物学和计算建模的努力，包括金属离子活性位点组成的变化如何改变MBP亲和力的研究。在具体目标3中，我们将研究金属蛋白抑制剂对其靶酶的选择性。我们将评估金属蛋白抑制剂在竞争金属蛋白存在下的活性，并研究用金属酶抑制剂治疗如何扰乱活细胞中的金属离子稳态。最后，我们将继续帮助世界各地的研究人员，针对新的金属蛋白靶点筛选我们的文库，并开发子文库，将这些努力从击中到领先。

 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.