Chapter 12 Structure-Based Lead Optimization

Publisher Summary This chapter discusses the different aspects of structure-based lead optimization. Structure-based drug design is an increasingly integral part of the drug discovery process. As the number of therapeutic targets with structural information dramatically increases, computational drug design methods continue to advance to make it possible for the pharmaceutical industry to achieve greater efficiency. New leads for a therapeutic target can be generated through (1) known inhibitors for the target or a much related target, (2) high-throughput screening (HTS) of corporate compound collections, or (3) the screening of natural product libraries. The way the leads are generated and the characteristics of the leads will determine to an extent the optimization strategy that is subsequently employed. A commitment of resources to transfer the biological assay to HTS format, run the screen, confirm statistically significant hits, analyze the results, and follow up with secondary assays must be in place. Structure-based virtual screening or molecular docking uses a heuristic to orient each database ligand in the binding site of the target structure and then scores each orientation.