Chemistry Reference
In-Depth Information
10
Capture Methods for
Fragment-based Discovery
Stig K. Hansen and Daniel A. Erlanson
10.1
Introduction
During the past decade, fragment-based lead discovery techniques have become more
widely used and are now often applied in conjunction with traditional high-throughput
biochemical screening (HTS). While HTS remains a very productive method for finding
chemical ligands, fragment-based lead discovery, in which leads are built progressively by
expanding or combining small pharmacophores, offers unique opportunities to discover
novel and unusual chemical starting points.
[
1, 2
]
Fragment-based approaches can identify
bindingmodes and interactions that may not be accessible to larger preassembledmolecules
that often contain multiple pharmacophores. In addition, fragment-based discovery often
leads to the synthesis of compounds that are non-obvious and structurally more diverse,
thereby complementing the chemotypes that may be found in HTS libraries. The main
challenge with this discovery approach lies in identifying and assembling the fragments.
Here we review the concept of covalent and dative fragment capture, where a bond is used
to stabilize the interaction between a weak fragment and a target protein, and describe how
these techniques can facilitate fragment-based lead discovery.
