Quantification of free ligand conformational preferences by NMR and their relationship to the bioactive conformation.

ABSTRACT: Accurate unbound solution 3D-structures of ligands provide unique opportunities for medicinal chemistry and, in particular, a context to understand binding thermodynamics and kinetics. Previous methods of deriving these 3D-structures have had neither the accuracy nor resolution needed for drug design and have not yet realized their potential. Here, we describe and apply a NMR methodology to the aminoglycoside streptomycin that can accurately quantify accessible 3D-space and rank the occupancy of observed conformers to a resolution that enables medicinal chemistry understanding and design. Importantly, it is based upon conventional small molecule NMR techniques and can be performed in physiologically-relevant solvents. The methodology uses multiple datasets, an order of magnitude more exper

SUBMITTER: Blundell CD 

PROVIDER: S-EPMC3744816 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature