Systematic assessment of fragment identification for multi‐target drug design

Designed multi-target ligands are a popular approach to generate efficient and safe drugs and fragment-based strategies have been postulated as a versatile avenue to discover multi-target ligand leads. To systematically probe the potential of fragment-based multiple ligand discovery, we have employed a large fragment library for comprehensive screening on five targets chosen from proteins for which multi-target ligands have been successfully developed previously (soluble epoxide hydrolase, leukotriene A4 hydrolase, 5-lipoxygenase, retinoid X receptor, farnesoid X receptor). Differential Scanning Fluorimetry served as primary screening method before fragments hitting at least two targets were validated in orthogonal assays. Therein, we obtained valuable fragment leads with dual-target engagement for six out of ten target combinations. Our results demonstrate the applicability of fragment based approaches to identify starting points for polypharmacological compound development with certain limitations.