Fragment Libraries Designed to Be Functionally Diverse Recover Protein Binding Information More Efficiently Than Standard Structurally Diverse Libraries

Current fragment-based drug design relies on the efficient exploration of chemical space by using structurally diverse libraries of small fragments. However, structurally dissimilar compounds can exploit the same interactions and thus be functionally similar. Using three-dimensional structures of many fragments bound to multiple targets, we examined if a better strategy for selecting fragments for screening libraries exists. We show that structurally diverse fragments can be described as functionally redundant, often making the same interactions. Ranking fragments by the number of novel interactions they made, we show that functionally diverse selections of fragments substantially increase the amount of information recovered for unseen targets compared to the amounts recovered by other methods of selection. Using these results, we design small functionally efficient libraries that can give significantly more information about new protein targets than similarly sized structurally diverse libraries. By covering more functional space, we can generate more diverse sets of drug leads.