Chemistry Reference
In-Depth Information
of the major limitations of covalent capture methods is the availability of a reactive residue
or the ability to engineer a reactive residue at the site of interest. The use of covalent capture
methods also requires an investment in custom fragment libraries with reactive functional
groups. The covalent linkage itself may provide some limitations with respect to the binding
orientations and interactions that can be surveyed from the attachment point, although this
limitation can be overcome by using multiple attachment points around the binding site of
interest.
10.6 Conclusions
Covalent capture methods have been primarily used to characterize protein-ligand inter-
actions and to discover novel ligands that bind to specific regions on a protein target.
Irreversible chemistries have been widely used to identify and characterize protein-ligand
interactions and for affinity labeling studies. By contrast, reversible capture methods have
primarily been used as screening techniques for protein-ligand and protein-small molecule
interactions for drug discovery. Tethering with extenders is probably the most sophisticated
of these methodologies by enabling
in situ
assembly of individual fragments in addition
to fragment selection. The ability to bypass the fragment linking process solves one of
the greatest challenges in combinatorial fragment assembly and opens the gates to probe a
much wider chemical diversity space with a minimal synthetic effort.
The past decade has seen significant advances in applying covalent capture technology
to fragment-based drug discovery, which is itself an emerging technology that has already
had a significant impact on the drug discovery process in many companies. Ultimately, the
success of these technologies will be judged by the impact they will have on delivering
successful clinical products.
10.7 Acknowledgments
We would like to thank Robert S. McDowell, Monya Baker and Michael Romanowski for
critical reading of the manuscript.
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