High-Confidence Protein–Ligand Complex Modeling by NMR-Guided Docking Enables Early Hit Optimization

Structure-based drug
design is an integral part of modern day drug
discovery and requires detailed structural characterization of protein–ligand
interactions, which is most commonly performed by X-ray crystallography.
However, the success rate of generating these costructures is often
variable, in particular when working with dynamic proteins or weakly
binding ligands. As a result, structural information is not routinely
obtained in these scenarios, and ligand optimization is challenging
or not pursued at all, representing a substantial limitation in chemical
scaffolds and diversity. To overcome this impediment, we have developed
a robust NMR restraint guided docking protocol to generate high-quality
models of protein–ligand complexes. By combining the use of
highly methyl-labeled protein with experimentally determined intermolecular
distances, a comprehensive set of protein–ligand distances
is generated which then drives the docking process and enables the
determination of the correct ligand conformation in the bound state.
For the first time, the utility and performance of such a method is
fully demonstrated by employing the generated models for the successful,
prospective optimization of crystallographically intractable fragment
hits into more potent binders.