Direct NMR Probing of Hydration Shells of Protein Ligand Interfaces and Its Application to Drug Design

Fragment-based drug design exploits
initial screening of low molecular
weight compounds and their concomitant affinity improvement. The multitude
of possible chemical modifications highlights the necessity to obtain
structural information about the binding mode of a fragment. Herein
we describe a novel NMR methodology (LOGSY titration) that allows
the determination of binding modes of low affinity binders in the
protein–ligand interface and reveals suitable ligand positions
for the addition of functional groups that either address or substitute
protein-bound water, information of utmost importance for drug design.
The particular benefit of the methodology and in contrast to conventional
ligand-based methods is the independence of the molecular weight of
the protein under study. The validity of the novel approach is demonstrated
on two ligands interacting with bromodomain 1 of bromodomain containing
protein 4, a prominent cancer target in pharmaceutical industry.