Combinatorial libraries model

Taylor, E.W., Giboons, J.A., and Baeck-man, R.A. Intestinal absorption screening of mixtures from combinatorial libraries in the Caco-2 model. Pharm. Res. 1997, 14, 572-577. 

Waldman M, Li H, Hassan M. Novel algorithms for the optimization of molecular diversity of combinatorial libraries. / Mo/ Graph Model 2000 18 412-26. 

Two main factors have guided the need for optimization of the early screening techniques on one hand the use of simple, quick and high-capacity cell monolayer methods, e.g., Caco-2 cell and MDCK and on the other hand the increased synthesis of more lipophilic, insoluble compounds from combinatorial libraries. This has created a vast number of different variants of cell-based assays and has resulted in variability among the data obtained. A need for optimization of as many as possible of the different parameters in order to increase the predictivity and throughput of the model has been suggested in the literature [98-100]. 

Quantitative Structure-Activity Relationship models are used increasingly in chemical data mining and combinatorial library design [5, 6]. For example, three-dimensional (3-D) stereoelectronic pharmacophore based on QSAR modeling was used recently to search the National Cancer Institute Repository of Small Molecules [7] to find new leads for inhibiting HIV type 1 reverse transcriptase at the nonnucleoside binding site [8]. A descriptor pharmacophore concept was introduced by us recently [9] on the basis of variable selection QSAR the descriptor pharmacophore is defined as a subset of... 

Brown RD, Hassan M, Waldman M. (2000) Combinatorial library design for diversity, cost efficiency, and drug-like character. /. Mol. Graph. Model. 18 427-437. 

Smith JR, Kholodovych V, Knight D, Welsh WJ, Kohn J (2005) QSAR models for the analysis of bioresponse data from combinatorial libraries of biomaterials. QSAR Comb Sci 24 99-113... 

Beavers, M. B. and Chen, X. (2002) Structure-based combinatorial library design methodologies and applications. J. Mol. Graph. Model. 20, 463-468. 

Computational models relating molecular structure and/or properties to biological activity are required for the design of both target-focused and target class combinatorial libraries based on known active ligands. These models are developed from descriptors, which encode information about molecular properties... 

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%]. 

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