Systematic Assessment of Fragment Identification for Multitarget Drug Design.
Arachidonate 5-Lipoxygenase
/ metabolism
Dose-Response Relationship, Drug
Drug Design
Enzyme Inhibitors
/ chemical synthesis
Epoxide Hydrolases
/ antagonists & inhibitors
Humans
Molecular Structure
Receptors, Cytoplasmic and Nuclear
/ antagonists & inhibitors
Retinoid X Receptors
/ antagonists & inhibitors
Structure-Activity Relationship
differential scanning fluorimetry
fragment-based drug design
multitarget drugs
polypharmacology
Journal
ChemMedChem
ISSN: 1860-7187
Titre abrégé: ChemMedChem
Pays: Germany
ID NLM: 101259013
Informations de publication
Date de publication:
08 04 2021
08 04 2021
Historique:
received:
04
11
2020
pubmed:
8
12
2020
medline:
29
12
2021
entrez:
7
12
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33283450
doi: 10.1002/cmdc.202000858
pmc: PMC8049054
doi:
Substances chimiques
Enzyme Inhibitors
0
Receptors, Cytoplasmic and Nuclear
0
Retinoid X Receptors
0
farnesoid X-activated receptor
0C5V0MRU6P
Arachidonate 5-Lipoxygenase
EC 1.13.11.34
Epoxide Hydrolases
EC 3.3.2.-
leukotriene A4 hydrolase
V38765PUZ6
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1088-1092Subventions
Organisme : German Research Foundation
ID : DFG
Organisme : German Research Foundation
ID : PR1405/2-2
Organisme : German Research Foundation
ID : PR1405/4-1
Organisme : German Research Foundation
ID : SFB1039
Organisme : German Research Foundation
ID : Teilprojekt A07
Organisme : German Research Foundation
ID : Teilprojekt A02
Informations de copyright
© 2020 The Authors. ChemMedChem published by Wiley-VCH GmbH.
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