Fragment libraries filters

SeeDs-2 library was generated from their in-house database called rCat of 1,622,763 unique chemical compounds assembled from 23 suppliers (25). The filtering cascade began with MW (same as SeeDs-1), then the functional groups and solubility filters which resulted in 43 unique compounds (no overlap with SeeDs-1). These were then clustered by 2D, 3-point pharma-cophoric features to provide 3 clusters, and the centroids of each cluster was submitted for chemist review. Of the 395 selected compounds that were ordered, 357 passed QC to become the SeeDs-2 fragment library. 

The final library was designed with the purpose of adding incremental diversity to the first three fragment libraries. The main filtering criterion was novel pharmacophoric triangles not found in the first three libraries. After clustering and visual inspection from a panel of medicinal chemists, only 65 compounds were purchased and 61 compounds passed QC. 

In cases where fragments, rather than compounds, are used to design libraries, the fragments may be filtered based on the nature of the binding site and their ability to adhere to existing chemistry protocols with respect to their attachments to templates or other fragments (58). Other filtering criteria... 

Key words Fragment-based lead discovery, screening collection, library design, computational filtering, NMR screening... 

A fully automated system uses either cDNA fragments of known genes or libraries of oligonucleotides, which are then spotted in duplicate onto hybridization filters (nylon membranes or PVDF) with a grid for guidance. When nylon membranes are used, these filters in microarrays can be used several times. There are two possible ways of applying the DNA to the filter (Cahill, 2001) ... 

In order to meet our requirements for a relatively large fragment screening library to maximise the potential of the HTFS concept, it was necessary to relax the upper limit on MW in order to access sufficiently diverse compounds. A final MW filter was applied to allow only compounds with MW in the range 150-350 Da. This MW range is slightly broader than used by others (Table 3.2). 

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