Journal article
Structural Studies of Bcl-xL/ligand Complexes using super(19)F NMR
Journal of biomolecular NMR, Vol.34(4), pp.221-227
04/01/2006
DOI: 10.1007/s10858-006-0005-y
Abstract
Fluorine atoms are often incorporated into drug molecules as part of the lead optimization process in order to improve affinity or modify undesirable metabolic and pharmacokinetic profiles. From an NMR perspective, the abundance of fluorinated drug leads provides an exploitable niche for structural studies using super(19)F NMR in the drug discovery process. As super(19)F has no interfering background signal from biological sources, super(19)F NMR studies of fluorinated drugs bound to their protein receptors can yield easily interpretable and unambiguous structural constraints. super(19)F can also be selectively incorporated into proteins to obtain additional constraints for structural studies. Despite these advantages, super(19)F NMR has rarely been exploited for structural studies due to its broad lines in macromolecules and their ligand complexes, leading to weak signals in super(1)H/ super(19)F heteronuclear NOE experiments. Here we demonstrate several different experimental strategies that use super(19)F NMR to obtain ligand-protein structural constraints for ligands bound to the anti-apoptotic protein Bcl-xL, a drug target for anti-cancer therapy. These examples indicate the applicability of these methods to typical structural problems encountered in the drug development process.
Details
- Title: Subtitle
- Structural Studies of Bcl-xL/ligand Complexes using super(19)F NMR
- Creators
- Liping Yu - Discovery LaboratoriesPhilip Hajduk - AbbottJamey Mack - AbbottEdward Olejniczak - Abbott
- Resource Type
- Journal article
- Publication Details
- Journal of biomolecular NMR, Vol.34(4), pp.221-227
- DOI
- 10.1007/s10858-006-0005-y
- ISSN
- 0925-2738
- eISSN
- 1573-5001
- Language
- English
- Date published
- 04/01/2006
- Academic Unit
- Biochemistry and Molecular Biology; Medicine Administration
- Record Identifier
- 9984627211002771