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.