Scaffold-based diversity selection

A third approach is to select a diverse set of scaffolds as opposed to picking diverse analogs within a single series. Diverse scaffolds can be chosen on the basis of 2D or 3D similarity metrics. In addition, several groups have also developed methods for evaluating the diversity of scaffolds based on the spatial placement of side chains. ... 

Finally, we mentioned in an earlier section the concept of classifying scaffolds based on the 3D diversity of their side-chain vectors. We can combine the same side-chain vector information with data about the active site and select only those compounds which have appropriate vectors to fill the pockets of interest. This can greatly reduce the number of compounds we need to dock. 

Hence there are multiple solutions for the final set of 10000 compounds. The final selection can be diversity driven using for example cluster analysis based on multiple fingerprints [63], hole filling strategies by using scaffold/ring analysis (LeadScope [66], SARVision [66]) or pharmacophore analysis [67, 68]. For a review of computational approaches to diversity and similarity-based selections, see the paper of Mason and Hermsmeier [69] and the references therein. 

The 5 k actives with percent inhibition of 25 to 40% and that feU into clusters of less than five compounds were treated separately using BCUT diversity analysis, as described in Section 6.2.5. A cell-based selection biased by primary activity from six bins per each of six axes yielded 1258 compounds. The combined selection from filtering, clustering, and diversity totaled 6986 compounds representing 3337 ring scaffolds and was submitted for confirmation assays. Note that the full set of 16 k filtered actives contained 9254 ring hashcodes, so the selected set covers 36.1% of the represented scaffolds. Because of the presence of duplicate samples in the corporate screening collection, 7275 samples were pulled and assayed. 

Derivatization of functional groups in a natural-product scaffold can also be effectively performed on the solid-phase. An example of this is the synthesis of a small compound collection (27-compounds) based on the tetrahydroquinoline scaffold. A chiral tetrahydroquinoline scaffold was synthesized in solution from 5-hydroxy-2-nitrobenzaldehyde (Scheme 4). The synthesis involved a key asymmetric aminohydroxylation step. This building block was anchored to the solid support with a Wang linker and diversity was introduced by selective deprotection and derivatization of the protected hydroxyl and amino substituents. 

The selections of compounds are made using a variety of methods, such as dissimilarity selection (16), optiverse library selection (17), Jarvis-Park clustering (18), and cell-based methods (19). All these methods attempt to choose a set of compounds that represent the molecular diversity of the available compounds as efficiently as possible. A consequence of this is that only a few compounds around any given molecular scaffold may be present in a HTS screening... 

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