Chemistry Reference
In-Depth Information
ordered). In general, the purities are consistently satisfactory and the number of dropouts
due to unconfirmed structure was spread evenly over the prioritised list of vendors that were
used. However, this may be due to the fact that vendors for which we previously have had
poor experience were not considered to be suitable suppliers in the first place or it might
be due to the industry-wide efforts to improve compound quality in recent years.
3.5 Conclusion
The techniques for fragment screening by NMR and high-concentration biochemical assay
are complementary.
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Evotec's NMR fragment library was built up independently from the
fragment library for high-concentration biochemical assays when the NMR group was part
of another organisation. Evotec has assembled one of the largest fragment collections to be
used on a routine basis for NMR fragment screening and high-concentration biochemical
assay screening. The philosophy for library construction for NMR fragment screening is
somewhat different to that adopted for the library for biochemical screening, but this has led
to two highly complementary libraries with minimal overlap (less than 1000 compounds
in common). Both libraries have been tailored to allow rapid fragment hit follow-up and
both collections are used for internal and external projects on a number of targets, so far
with highly promising results. We have found that the use of these two fragment librar-
ies has favourably shifted lead discovery activities at Evotec towards lower MW starting
points, where chemical optimisation is faster and less resource consuming, especially when
advantage is taken of structural insights gained though detailed NMR analysis and/or X-ray
crystallography of fragments in complexes with target proteins.
3.6 Abbreviations
CDK2
cyclin-dependent kinase-2
CMC
comprehensive medicinal chemistry
Da
dalton
DMSO
dimethyl sulfoxide
DNA
deoxyribonucleic acid
F2L
fragment-to-lead
FBDD
fragment-based drug discovery
GaP
gridding and partitioning
HBA
hydrogen bond acceptor
HBD
hydrogen bond donor
HTFS
high-throughput fragment screening
HTS
high-throughput screening
IP
intellectual property
LC-MS
liquid chromatography-mass spectrometry
MW
molecular weight
NHC
non-hydrogen atom count
NMR
nuclear magnetic resonance
PTP1B
protein tyrosine phosphatase 1B
