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.