Chemistry Reference
In-Depth Information
5
Application of Protein-Ligand NOE
Matching to the Rapid Evaluation
of Fragment Binding Poses
William J. Metzler, Brian L. Claus, Patricia A. McDonnell, Stephen R. Johnson, Valentina
Goldfarb, Malcolm E. Davis, Luciano Mueller and Keith L. Constantine
5.1
Introduction
'Fragments', or low molecular weight compounds, are increasingly being recognized as
attractive starting points for deriving novel, potent inhibitors against an expanding array
of therapeutic targets. Since the first reports of fragment-based screening by the Abbott
biomolecular NMR laboratory,
[
1
]
where it was demonstrated that a structure-guided com-
bination of fragments can yield a progressable lead series, numerous examples detailing
the development of fragments into mature drug candidates have been documented (see
ref. 2 for a review). The benefits of fragments are numerous. The low complexity of frag-
ments results in a statistically high probability of their pharmacophores matching those in
the target protein's binding site.
[
3
]
Hence fewer fragments need to be screened in order to
identify a 'hit'. The result of this is that fragment screening libraries can be composed of
a relatively small number of compounds, typically on the order of only several hundred
to several thousand. Although their absolute binding affinities tend to be low, fragment
hits are generally efficient binders, that is, they tend to have high binding affinities relat-
ive to their heavy atom counts. This is because a high proportion of their atoms usually
make favorable interactions with the receptor. Furthermore, the simplicity of fragments
makes them highly amenable to optimization, since additional functionality can be added
