TY  - JOUR
A1  - Brunst, Steffen
A1  - Kramer, Jan S.
A1  - Kilu, Whitney
A1  - Heering, Jan Peter
A1  - Pollinger, Julius
A1  - Hiesinger, Kerstin
A1  - George, Sven
A1  - Steinhilber, Dieter
A1  - Merk, Daniel
A1  - Proschak, Ewgenij
T1  - Systematic assessment of fragment identification for multitarget drug design
T2  - ChemMedChem
N2  - 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.
KW  - differential scanning fluorimetry
KW  - fragment-based drug design
KW  - multitarget drugs
KW  - polypharmacology
Y1  - 2020
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/63869
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-638697
SN  - 1860-7187
N1  - This research was supported by the German Research Foundation (DFG; PR1405/2-2, PR1405/4-1, SFB1039, Teilprojekt A07 and Teilprojekt A02) Open access funding enabled and organized by Projekt DEAL.
VL  - 16
IS  - 7
SP  - 1088
EP  - 1092
PB  - Wiley-VCH
CY  - Weinheim [u.a.]
ER  -