Chemistry Reference
In-Depth Information
7
In Situ
Fragment-based Medicinal
Chemistry: Screening by Mass
Spectrometry
Sally-Ann Poulsen and Gary H. Kruppa
7.1
Introduction
The task of discovering and then optimizing small molecules that interact with and appro-
priately modify the activity of large biomolecules such as enzymes is central to the forward
progression of the drug discovery pipeline. To transform a small molecule lead into a safe
medicine that can be used in people requires conquering a broad spectrum of challenges
and it is unsettling that massive investment by the pharmaceutical industry in research
efficiencies and platform technologies has not equated with improving the speed of drug
discovery.
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1
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While the reasons behind this limited success are complex and varied (and out-
side the scope of this chapter), the situation does provide grounds for the industry to address
urgently the effectiveness of current medicinal chemistry programmes and to consider
exploring alternative avenues for improving the quality of lead discovery outcomes.
Identification of new drug leads by fragment-based screening now has its foundations
firmly established as a valuable tool to facilitate drug discovery, and this is evidenced by the
content of this topic. Target-templated synthetic approaches that covalently link fragments
within the confines of a target's binding site have developed alongside themodern fragment-
based screening and fragment-based drug discovery concepts. These synthetic approaches
include
in situ
dynamic combinatorial chemistry (DCC) and
in situ
Click chemistry.
In situ
