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Systematic Assessment of Fragment Identification for Multitarget Drug Design
Author(s) -
Brunst Steffen,
Kramer Jan S.,
Kilu Whitney,
Heering Jan,
Pollinger Julius,
Hiesinger Kerstin,
George Sven,
Steinhilber Dieter,
Merk Daniel,
Proschak Ewgenij
Publication year - 2021
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.202000858
Subject(s) - fragment (logic) , epoxide hydrolase 2 , drug discovery , computational biology , ligand (biochemistry) , chemistry , virtual screening , combinatorial chemistry , computer science , receptor , biochemistry , biology , enzyme , algorithm
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.