SAR Analysis/Med Chem (Florida)

初始SAR分析的目标是以一种允许 对哪种改性(S)可能导致性能改善的合理预测。因此，这种分析是 与化学家紧密结合，开发出结构优化的工作假设和策略。每个人 将根据效价(生化/细胞)、选择性、溶解性、生物利用度、 毒性大，易于合成。将为每个班级确定问题。先导化合物选自 用最理想的配置文件和合理的SAR命中类进行进一步改进。如果这些实验性的 没有可用的数据，计算描述符和模型可以用来评估一个结构 类比另一个类更易于优化。我们还将考虑绑定效率指数(BEI)和 表面结合效率指数(SEI)。[65]在生产阶段，我们计划实施一些 使用各种滤波器的用于这种多维SAR和SPR分析的附加计算工具， 模型和可视化技术，以快速和可重复地对化学系列或单个化合物进行排序 在探测器开发项目的背景下。 随着探针优化通过迭代循环进行，对S1P受体进行的分析也包括在内 定量构效关系、药效团模型开发和对接研究。基于受体结构的设计将是 如果靶结构已知或可以建立靶受体的合理同源模型，则应用该方法。 行业标准的基于药效团和形状的建模和可视化工具可用，并且 在信息学和资源部分进行了描述。在这种情况下，每类点击都将停靠到 受体结构寻找可能的作用模式(结合模式)。最受欢迎的行动模式应该是 与最初的搜救结果一致。最初的SAR、受体结构信息(如果有)和经验 药物化学将结合在第二代分子的设计中，以克服至少一些 主导班的问题。这些化合物将经过筛选和剖析。这些数据将被用于提炼 SAR又被应用于下一代文库的设计，直到优化化合物/探针 都得到了。根据表7中的定义，优化后的导联应在初始命中的基础上改进。所有探头和 他们的相关数据将根据已公布的RFA指南提供给所有研究人员。

The goal of an initial SAR analysis is to understand the influence of structural changes in a way that allows a reasonable prediction of which modification(s) may lead to improved properties. This analysis is therefore tightly coupled with the chemists developing a working hypothesis and strategy for structure optimization. Each class of hits will be profiled based on potency (biochemical/cellular), selectivity, solubility, bioavailability, toxicity, and ease of synthesis. Issues will be identified for each class. Lead compounds are chosen from the hit classes with the most desired profiles and sensible SAR for further improvement. If these experimental data are not available, computational descriptors and models can be used to assess whether one structural class is more amenable to optimization than another. We will also consider binding efficiency index (BEI) and surface binding efficiency index (SEI). [65] For the production phase we plan to implement a number of additional computational tools for such multidimensional SAR and SPR analyses using a variety of filters, models, and visualization techniques to quickly and reproducibly rank chemical series or individual compounds in the context of the probe development project. As the probe optimization proceeds through iterative cycles, analyses performed for S1P receptors incjuded QSAR, pharmacophore model development, and docking studies. Receptor structure-based design will be applied if the target structure is known or a reasonable homology model of the target receptor can be built. Industry standard pharmacophore- and shape-based modeling and visualization tools are available, and are described in the informatics and resources section. In this case, each class of hits will be docked to the receptor structure to find possible mode of action (binding mode). The favored mode of action should be consistent with the initial SAR. The initial SAR, receptor structural information (if available), and experience in medicinal chemistry will be combined in the design of second-generation molecules to overcome at least some of the issues of lead classes. The compounds will be screened and profiled. The data will be utilized to refine the SAR which in turn is applied in the design of next generation libraries until optimized compounds/probes are obtained. The optimized lead should be improved over the initial hit as defined in Table 7. All probes and their associated data will be made available to all researchers in accordance with the published RFA guidance.