Combinatorial libraries design

The discovery of this lead compound as a potent PDF inhibitor was a result of an integrated combinatorial and medicinal chemistry approach based on the proposed generic PDF inhibitor structure. This focused chemical library was designed by Chen et al. [79], and was prepared using solid-phase parallel synthesis in which 22 amines and 24 amino acids were used as building blocks, as outlined in Scheme 23. 

The SHAPES Linking Library was designed to facilitate the use of combinatorial chemistry to follow up screening hits [11]. This library consists primarily of commercially available compounds containing two drug-like scaffolds connected by a linkage that is synthetically accessible. To construct this library, a database of commercially available compounds was filtered to select for drug-likeness and the presence of the desired molecular... 

Bradley and coworkers used the 3D pharmacophore ensemble model to filter a virtual combinatorial library of 3924 N-substituted glycine peptoids (30) containing three known a, actives down to a set of 639 products. Using a cut-down technique, a 160 compound combinatorial library was designed in which the number of compounds that passed the ensemble model filter was maximized. This library contained two of the three known actives present in the original 3924 compound virtual library. This represents a substantial enrichment [(2 actives/160 products) X 100 = 1.25% vs (3 actives/3924 products) x 100 = 0.076%]. 

Zhou, J. Z., Shi, S., Na, J., Peng, Z., Thacher, T. (2009) Combinatorial library-based design with basis products. J Comput Aided MolDes2S, 725-736. 

The diverse combinatorial screening described in the previous sections revealed active Pt-Ru-Co methanol oxidation catalysts, especially near Pt20Co6oRu2o. A second primary screening cycle (Fig. 11.8) focused on a more limited compositional space to isolate the active region in more detail. Figs. 11.15 and 11.16 show the design and the sampled compositional space of a Pt-Ru-Co ternary library. The design contains a pure Pt catalyst, Pt-Co binaries (row A), Pt-Ru binaries (column 1)... 

Burello E., Frecer V, Miertus S, Combinatorial design and focusing of library of cyclic urea inhibitors of aspartic protease of HIV-1, chem. Biochem. submitted. 

The next sections describe several specific examples of how the full range of computational methods have been used to design libraries, ranging from methods using only 2-D structural descriptors, to complete structure-based combinatorial design. 

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