Virtual combinatorial library library

In general, the described techniques provide an effective, flexible, and relatively fast solution for library design based on analysis of bioscreening data. The quantitative relationships, based on the assessment of contribution values of various molecular descriptors, not only permit the estimation of potential biological activity of candidate compounds before synthesis but also provide information concerning the modification of the structural features necessary for this activity. Usually these techniques are applied in the form of computational filters for constraining the size of virtual combinatorial libraries and... 

Makino S, Ewing TJ, Kuntz ID. DREAM-r-i- flexible docking program for virtual combinatorial libraries. J Comput Aided Mol Des 1999 13 513-32. 

J.-M. Lehn, Dynamic Combinatorial Chemistry and Virtual Combinatorial Libraries , Chem. Eur. J. 1999, 5, 2455-2463. 

Virtual combinatorial compound libraries can be constructed and docked against the target [40 2]. This latter approach is likely to be more suitable for the fragment-optimization phase of a project, when the virtual library can be constructed around an initial fragment hit, with varying substitution patterns on pre-defined attachment points. The compounds can then be docked either in an imrestrained fashion, or, more usefully, using the 3D structure of the initial hit as a constraint or restraint [35]. 

Making, S., Ewing, T.J.A., Kuntz, I.D. DREAM4—p Flexible docking program for virtual combinatorial libraries. 

Oprea, T.I. Rapid estimation ofhydro-phobicity for virtual combinatorial library analysis. SAR and QSAR Environ. Res. 2001, 12, 129-141. 

Fig. 12.8 Ge neral procedures of selection of a rational target-specific subset within an initial virtual combinatorial library.

In general, reagent-based selection is much faster and more convenient to execute in the laboratory as compared with the product-based selection. On the other hand, the latter strategy usually provides more accurate results. There exists a potential to combine both approaches to achieve more optimal results, particularly in the case of large exploratory virtual combinatorial libraries, for which mass random synthesis and screening are not economically feasible. In this article, we demonstrated the usefulness of property-based approach for selection of optimal GPCR ligands. 

Hue, I. Lehn, J. M. Virtual combinatorial libraries Dynamic generation of molecular and supramolecular diversity by self-assembly. Proc. Natl. Acad. Sci. U.S.A. 1997,94,2106-2110. 

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%]. 

Lehn JM. Dynamic combinatorial chemistry and virtual combinatorial libraries. Chem Eur J 1999 5 2455-2463. 

Stimulated by the widespread applications of HTS technologies, combinatorial chemistry has provided a powerful tool for rapidly adding large number of compounds to corporate collections for many pharmaceutical companies. Virtual combinatorial library consists of libraries from individual reactions and compounds from a single reaction share a common product core (see Fig. 2.3). The number of compounds in a combinatorial library can grow rapidly with number of reaction components and numbers of reactants for individual components. For example, a full combinatorial library from a three-component reaction... 

Fig. 2.3. Virtual combinatorial library is the start point for any combinatorial library design. It consists of libraries from individual reactions. Compounds from a given reaction share a unique product core.

Schneider, G. (2002) Trends in virtual combinatorial library design. Curr Med Chem 9, 2095-2101. 

Key words Virtual combinatorial library, Markush technique, compound analysis, chemoinfor-... 

Generation of a virtual combinatorial library by finding substituents of a custom scaffold that can be accommodated in the binding site of a molecular target or meet other 3D structural criteria. Once the virtual library is synthesized in the computer, individual members can be selected using structural or additional criteria and synthesized using automated equipment. 

Varnek, A., Fourches, D., Solov ev, V.P. et al. 2004. In Silico design of new uranyl extractants based on phosphoryl-containing podands QSPR studies, generation and screening of virtual combinatorial library and experimental tests. J. Chem. Inf. Comput. Sci. 44 (4) 1365-1382. 

A screening of the virtual combinatorial library was performed in several steps. As potential extractants must be insoluble in the water phase, the ISIDA-Log S module incorporating QSPR models for aqueous solubilities (log S)95 has been used for filtering the library. Thus, the compounds for which log S < -3 were considered insoluble in water other compounds were excluded. A subset containing 9,306 potentially insoluble molecules has been screened using the structure-log D models. The main goal of screening was the selection of potentially efficient extractants. However, in... 

Hochgurtel, M., Kroth, H., Piecha, D., Hofmann, M. W., Nicolau, C., Krause, S., Schaaf, O., Sonnenmoser, G. and Eliseev, A. V. (2002). Target-induced formation of neuraminidase inhibitors from in vitro virtual combinatorial libraries. Proc. Natl. Acad. Sci. USA 99, 3382-3387. 

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