Chemistry Reference
In-Depth Information
6
Target-immobilized NMR Screening:
Validation and Extension to
Membrane Proteins
Virginie Früh, Robert J. Heetebrij and Gregg Siegal
6.1
Introduction
Fragment-based drug discovery (FBDD) methods have been widely embraced in the last
few years. Nearly all of the major pharmaceutical firms have developed fragment screening
and evolution programs and a number of biotech firms have sprung up that make exclusive
use of the approach to develop small-molecule therapeutics. Among the variety of frag-
ment screening and evolution methods that have been implemented, there are two common
themes. First, the collection of compounds to be screened consists of small (typically less
than 300 Da), highly soluble molecules. As such, they typically interact with the target
weakly, with binding constants in the range 2-5000 μM. Second, the low-affinity hits dis-
covered by screening such a collectionmust be developed into high-affinity, high-specificity
ligands. This process is much more successful when 3D structures of target-compound
complexes are available. [ 2 ]
The promise of FBDD, that is, compounds that through obeying Lipinski's rules [ 3 ] are
more likely to make orally bioavailable, safe drugs, is starting to be put to the test as
compounds begin to move into clinical trials. The number of such compounds is rising
rapidly due to the successes of Plexxikon, Astex, Sunesis, SGX Pharma and a host of
other biotech companies that place FBDD at the core of their activities. However, a third
common theme that applies to all FBDD to date is that is has been strictly applied to
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