Systematic assessment of fragment identification for multitarget drug design

  • 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.
Author:Steffen Brunst, Jan S. Kramer, Whitney KiluGND, Jan Heering, Julius Pollinger, Kerstin Hiesinger, Sven George, Dieter SteinhilberORCiDGND, Daniel MerkORCiDGND, Ewgenij ProschakORCiDGND
Parent Title (English):ChemMedChem
Place of publication:Weinheim [u.a.]
Document Type:Article
Date of Publication (online):2020/12/06
Date of first Publication:2020/12/06
Publishing Institution:Universit├Ątsbibliothek Johann Christian Senckenberg
Release Date:2022/03/16
Tag:differential scanning fluorimetry; fragment-based drug design; multitarget drugs; polypharmacology
Page Number:5
First Page:1088
Last Page:1092
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.
Institutes:Biochemie, Chemie und Pharmazie
Dewey Decimal Classification:5 Naturwissenschaften und Mathematik / 54 Chemie / 540 Chemie und zugeordnete Wissenschaften
6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung 4.0