Fragment libraries designed to be functionally diverse recover protein binding information more efficiently than standard structurally diverse libraries

Abstract

Current fragment-based drug design relies on the efficient exploration of chemical space though the use of structurally diverse libraries of small fragments. However, structurally dissimilar compounds can exploit the same interactions on a target, and thus be functionally similar. Using 3D structures of many fragments bound to multiple targets, we examined if there exists a better strategy for selecting fragments for screening libraries. 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 other methods of selection. Using these results, we design small functionally efficient libraries that are able to give significantly more information about new protein targets than similarly sized structurally diverse libraries. By covering more functional space (rather than chemical space), more diverse sets of drug leads can be generated, increasing the chances of fragment screens resulting in viable drug candidates.