Core D: Drug Discovery

摘要-核心D 药物发现核心将是为项目1-3中的个别调查人员提供支助的资源 通过一个最先进的，合理设计的药物发现计划，为推定的临床前设计 抗炎和抗聚集剂。Core已经将近2500种化合物编目成两种 图书馆，另一个图书馆正在建设中。在生物检测的第一轮筛选之后 (项目1和3)，核心将在以前开发的“训练”算法(非线性)中使用结果数据 基于QSAR)用于硅胶成型的关键结构元素，在这一点上不会偏向于 任何已知的身份或结构。同时，核心将使用其现有的计算工具来设计 结构元素已知或预测为药效酮或IL-1受体的化合物 对抗者。ADMET信息将作为过滤器，合理选择具有药物性质的化合物 属性(如肠道吸收、血浆稳定性和血脑屏障通透性)。核心也将是 负责合成足够数量(放大)的最有前途的第二代 用于在细胞培养和体内实验中进一步评估的化合物。预计所有项目都将利用 用于评价作为具有相互作用能力的治疗剂的新分子实体的核心D设施 具有潜在的治疗优势，分别为炎症、蛋白质病、胰岛素抵抗三联症。

SUMMARY – CORE D The Drug Discovery Core will be a resource providing support for individual investigators in Projects 1-3 through a state-of-the-art, rational-design drug discovery program for early preclinical design of putative antiinflammatory and anti-aggregation agents. The Core already catalogs almost 2500 compounds in two libraries, and another library is under construction. After an initial round of screening in biological assays (Projects 1 and 3), the Core will use the resulting data in previously developed “training” algorithms (nonlinear QSAR based) for in silico molding of the key structural elements that will not be, at this point, biased toward any known identity or structure. In parallel, the Core will use its extant computational tools to design compounds with structural elements known or predicted to act as pharmacoperones or IL-1 receptor antagonists. ADMET information will be applied as a filter to rationally select compounds with druglike attributes (e.g., gut absorption, plasma stability, and blood-brain barrier permeability). The Core will also be responsible for synthesizing sufficient quantities (scaling-up) of the most promising second-generation compounds for further evaluation in cell-culture and in vivo experiments. All the Projects are expected to utilize Core D facilities for the evaluation of novel molecular entities as therapeutic agents having the ability to interact with the potential therapeutic priorties of each arm of the inflammation, proteinopathy, insulin-resistance triad.