Chemistry Reference
In-Depth Information
will then incorporate a biophysical technique either as the primary screen or to validate hits
obtained from an alternative source. NMR and X-ray crystallography are undoubtedly the
most popular approaches, as highlighted in ensuing chapters, requiring substantial invest-
ment in terms of skill base and technology. Drug discovery programmes, however, benefit
immensely from access to structural information at this critical stage, when the chemical
nature of the lead compounds is being decided, and thus structural biology can have a
significant positive impact on the speed and success of the programme.
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36
]
Effective dis-
semination of the information gained from a screen is also decisive both in understanding
the activity of the hit fragments and in their development. Here computational chemistry
and informatics tools can play a key role in integrating data across the different disciplines
in addition to directing the design of follow-up compounds. Development can follow one
of many strategies, from simple elaboration of single compounds, linking fragments from
adjacent regions in a binding site, focused libraries around one or more hits or to more com-
plex amalgamations of compounds observed to bind in overlapping regions of the binding
site. Having access to multiple structures of fragment-protein complexes is an invaluable
tool in this process; it can also provide a direct understanding of the protein binding site and
guide optimisation throughout the lifetime of the project. The final chapters will review the
use of computational methods in the overall process and then lead on to practical examples
of fragment-based drug discovery.
References
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