Chemistry Reference
In-Depth Information
value of combining fragment-based NMR screens with molecular docking to
generate chemical leads.
While fragment-based screens have been shown to be an effective approach to
drug discovery, NMR ligand affinity screens require more time and material than
a virtual screen. However, fragment-based screens are extremely helpful for new
therapeutic targets with unknown binding sites. Also, the approach has the added
benefit of providing information about the druggability of the protein target. There
is a correlation between the hit rate of a fragment-based NMR screen and the ability
of the protein target to bind drug-like compounds with high affinity [
176
,
177
].
5 Concluding Remarks
Significant advances continue to be made in the fields of molecular docking and
NMR ligand affinity screens that are benefiting drug discovery. Molecular docking
provides an extremely rapid way to evaluate likely binders from a large chemical
library with minimal cost. Unfortunately, limitations in the accurate ranking of true
binders by molecular docking programs require further experimental validation.
Conversely, NMR ligand-affinity screens can directly detect a protein-ligand
interaction, can measure a corresponding
K
D
, and can reliably identify the ligand
binding site. However, NMR-ligand affinity screens are resource intensive and are
generally limited to relatively small chemical libraries. Thus, the strengths and
weakness of virtual screens and NMR ligand affinity screens are perfectly comple-
mentary. Combining the two screening techniques has the potential of significantly
improving the efficiency of drug discovery. The combination of NMR and molecu-
lar modeling techniques has been shown to enable the rapid determination of
reliable protein-ligand co-structures, the identification of new therapeutic targets,
and the successful discovery of new drug leads.
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