Chemistry Reference
In-Depth Information
3
Assembling a Fragment Library
Mark Brewer, Osamu Ichihara, Christian Kirchhoff, Markus Schade
and Mark Whittaker
3.1
Introduction
The current popularity of fragment-based drug discovery (FBDD) represents a shift in
philosophy from the random screening of molecules with higher molecular weights and
physical properties more akin to those of drug-like compounds to the screening of smaller,
less complex molecules. This is because it has been recognised that fragment hit molecules
can be efficiently optimised into leads particularly if the binding mode to the target protein
has been first determined by 3D structural elucidation.
Several studies have shown that medicinal chemistry optimisation results in a final com-
pound with increased molecular weight compared with the starting structure. The evolution
of a low molecular weight fragment hit represents an attractive approach to optimisation
and may be more efficient than pruning back a higher molecular weight hit compound
discovered by conventional high-throughput screening of drug-like compound libraries.
Fragment hits represent a simpler molecular entry point to the drug discovery process com-
pared with, say, conventional high-throughput screening (HTS) hit molecules but owing to
their inherent simplicity often exhibit lower potencies than larger drug-like hit molecules.
Furthermore, there are cases where the screening of fragment libraries has yielded hits
where standard HTS has proven challenging; a recent example is the Alzheimer's disease
target -secretase. [ 1, 2 ] It has been argued, by consideration of 'ligand efficiency', [ 3, 4 ] that
fragments offer a more practical starting point for hit-to-lead and lead optimisation pro-
grammes. [ 4 ] Ligand efficiency has been developed from the concept of Kuntz et al . [ 5 ] on
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