Fragment-based Lead Discovery and Optimization Using X-Ray Crystallography, Computational Chemistry, and High-throughput Organic Synthesis

This chapter contains sections titled: Introduction Overview of the SGX Structure-driven Fragment-based Lead Discovery Process Fragment Library Design for Crystallographic Screening Considerations for Selecting Fragments SGX Fragment Screening Library Selection Criteria SGX Fragment Screening Library Properties SGX Fragment Screening Library Diversity: Theoretical and Experimental Analyses Crystallographic Screening of the SGX Fragment Library Overview of Crystallographic Screening Obtaining the Initial Target Protein Structure Enabling Targets for Crystallographic Screening Fragment Library Screening at SGX-CAT Analysis of Fragment Screening Results Factor VIIa Case Study of SGX Fragment Library Screening Complementary Biochemical Screening of the SGX Fragment Library Importance of Combining Crystallographic and Biochemical Fragment Screening Selecting Fragments Hits for Chemical Elaboration Fragment Optimization Spleen Tyrosine Kinase Case Study Fragment Optimization Overview Linear Library Optimization Combinatorial Library Optimization Discussion and Conclusions Postscript: SGX Oncology Lead Generation Program References