Combinatorial libraries biased

A list of privileged scaffolds - several of which are natural-product derived - for target-family-biased combinatorial libraries was recently presented by Muller [94], These scaffolds were proven to produce biologically active compounds for more than one member of a given target family. A rough-and-ready in-silico evaluation... 

Biased combinatorial libraries—novel ligands for the Sh3 do- 106. main of phosphatidylinositol 3-kinase. J. Am. Chem. Soc. 1993 115 12591-12592. 

Molecular diversity Synthetic and virtual molecule libraries used in combinatorial chemistry and high throughput screening can only be efficient if they contain as much information as possible. The molecular diversity should be comparable to the diversity of natural compounds. The first combinatorial libraries were biased during screening toward large, hydrophobic molecules, which led to poor bioavailability and the rule-of-5. 

Reagent-biased product design is now quite widely used and commonly the method of choice. " " The methods most commonly applied to measure diversity in large compounds sets (combinatorial libraries or screening collections) include 2D fingerprints (for substructural... 

Chen, J. K., Lane, W. S., Brauer, A. W., Tanaka, A., and Schreiber, S. L., Biased combinatorial libraries Novel ligands for the SH3 domain of phosphatidylinositol... 

We screened our libraries for the site-selective epoxidation of famesol (120) [182]. Either the peracid reagent /mCPBA, or catalytic n-alkyl acids, provided a benchmark for the intrinsic and poorly selective product distribution of monoepoxides (see Fig. 13b inset for schematic of famesol nomenclature). Hits from the initial libraries, however, showed selectivity toward 2,3-epoxide 121 and 6,7-epoxide 122, inspiring the development of biased combinatorial libraries to select further for these oxidation sites (Fig. 13b). Further optimization of the sequences after additional library sequences yielded peptide 123, which provided 2,3-epoxy famesol 121 with 1 1 >100 site selectivity (10,11 6,7 2,3) in 81% yield and 86% ee. These values are comparable to those provided for this substrate by the venerable Sharpless asymmetric epoxidation [187]. Optimization of the 6,7-biased sequence led to peptide 124, which provided 6,7-epoxy famesol 122 in 1.2 8.0 1.0 site selectivity (10,11 6,7 2,3) in 43% yield and 10% ee. Despite the modest ee of 122, we note that, to our knowledge, no existing catalytic epoxidation method is capable of providing 122 directly in reasonable purity. 

Flower plots are particularly useful in assessing the distribution of properties across a collection of compounds. Figure 5 shows the structures and associated flower plots of 18 side-chains from a biased /((-substituted glycine peptoid combinatorial library. The structures on the first row are tyramine... 

Figures Structures and flower plots of 18 side-chains form a biased -substituted glycine combinatorial library based on the tyramine submonomer (reproduced from J. Med. Chem., 1995, 38, 1431). The side-chains on the top row include tyramine and its five closest analogs. The 12 side-chains in the lower rows were chosen by D-optimal design from a pool of 721 amines...

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