Targeted Inhibitor Design: Lessons from Small Molecule Drug Design, Directed Evolution, and Vaccine Research

Inhibitors of protein-protein interactions are useful for elucidating novel biology and for manipulating biological processes for therapeutic effects. To this end, both small molecule and protein inhibitors are commonly used. The discovery of novel binders is most often accomplished by screening a diversity oriented library. However, preexisting biochemical and structural information on the target molecule is often neglected during the screen. Incorporating molecular details of the binding surface can improve the efficiency of discovering molecules with useful biological properties. We discuss how structural and other molecular data are leveraged to bias high throughput screen and optimize the efficiency of identifying high affinity, functional binders. Examples from small molecule drug design, protein engineering and vaccine research are used to illustrate the point.