Abstract:
:Designed multitarget ligands are a popular approach to generating efficient and safe drugs, and fragment-based strategies have been postulated as a versatile avenue to discover multitarget 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 multitarget 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. Thereby, 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.
journal_name
ChemMedChemjournal_title
ChemMedChemauthors
Brunst S,Kramer JS,Kilu W,Heering J,Pollinger J,Hiesinger K,George S,Steinhilber D,Merk D,Proschak Edoi
10.1002/cmdc.202000858subject
Has Abstractpub_date
2020-12-06 00:00:00eissn
1860-7179issn
1860-7187pub_type
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