Chemistry Reference
In-Depth Information
simply enhanced sets identified by virtual screening. At the opposite end, some fragments
may need to be removed from the original collection because they become unavailable,
IP protected or otherwise undesirable. Hence storage and compound handling automation
should allow flexible management of individual compounds wherever possible, rather than
being restricted to presorted compound mixtures or multiple compound containers.
3.4 Evotec's Library for HTFS
For our fragment screening activities by biochemical assays, we have built a library of
over 20 000 fragment compounds that have been carefully selected in three iterations by
applying a set of computational filters followed by review by a panel of medicinal chemists.
Evotec has coined the term High-Throughput Fragment Screening (HTFS) to describe
the screening of fragment molecules by high-concentration biochemical assays performed
on the EVOscreen uHTS platform. These techniques have been described elsewhere
[
24
]
and, in comparison with other fragment screening methods, library size is not limited by
throughput, enabling large fragment collections to be screened. Based on promising early
results with this technology, a decision was made to assemble a fragment library of 20 000
molecules. The team assigned to this effort was fortunate to be able to rely on long-term
experience and a well-established infrastructure for library assembly and maintenance for
the management of the in-house corporate HTS collection (currently over 250 000 unique
screening compounds).
The assembly of the fragment library was conducted in three iterations: (i) the Stage 1
library consisted of
∼
∼
5000 frag-
ments; and (iii) the Stage 3 library consists of over 20 000 fragments. The process that was
adopted for the selection (Figure 3.3) is related to that described above for the NMR library.
The similarities and differences in the approaches are apparent from the discussion below.
1200 fragments; (ii) the Stage 2 library was expanded to
3.4.1 Vendor Selection
The process for the selection of the fragment library for biochemical screening is based on a
database of Evotec's proprietary building blocks and compounds from selected commercial
vendors that is updated on a regular basis. Different subsets of vendors were selected for
the three phases, mainly according to their reliability, quality of their compounds and our
experience regarding delivery timelines. Although containing 35 different vendors, the
list for the final phase was restricted to the best 13 suppliers. More than 1 million records
(
∼
≤
350 Da were fed
into the selection process. The vendors that were prioritised for the selection of fragments
for the fragment library for biochemical screening were different to those selected for the
NMR library.
715 000 structures when duplicates were taken into account) withMW
3.4.2
Substructure Filters
An extensive range of in-house filters was applied to remove toxic, reactive and undesirable
functionality. This set of filters has been built up based on years of experience with HTS
screening and medicinal chemistry optimisation of hits to leads. A special focus was made
