Virtual combinatorial chemistry

Langer T, Wolber G. Virtual combinatorial chemistry and in silica screening efficient tools for lead structure discovery Pure Appl Chem 2004 76 991-6. 

Nowadays a broad range of methods is available in the field of chemoinfor-matics. These methods will have a growing impact on drug design. In particular, the discovery of new lead structures and their optimization will profit by virtual saeening [17, 66, 100-103]. The huge amounts of data produced by HTS and combinatorial chemistry enforce the use of database and data mining techniques. 

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

The selection of building blocks is based on information derived from, for example, computational chemistry, where potential virtual ligand molecules are modeled to fit the receptor-protein binding site. Combinatorial chemistry commences with a scaffold or framework to which additional groups are added to improve the binding affinity. Compounds are prepared and later screened using HTS. In this way, many compounds are tested within a short time frame to speed up drug discovery. 

The integration of combinatorial chemistry, structure-based library design and virtual screening [268, 269] also resulted in successful applications [270, 271]. It ultimately should result in broader SAR information about directionality and physicochemical requirements of acceptable building blocks. This concept is based on feasible scaffolds for exploring protein subsites using parallel or combinatorial synthesis. 

The nature of combinatorial chemistry can present a considerable challenge because these libraries are generally produced as arrays of compounds and it is often inconvenient to synthesize individual compounds in order to achieve an optimal design. Two methods have been described that attempt to select optimal subset of reagents from a virtual library that has been partitioned into favorable and unfavorable compounds by some method of filtering. The PLUMS algorithm [97] was designed to simultaneously optimize the size of the library based on effectiveness and efEciency . 

Virtual screening on a 2-D basis is far more efficient in terms of computing time, although the information content of the resulting virtual hits is far less sophisticated than for a 3-D pharmacophore search. It is in this setting that combinatorial chemistry approaches are applied most effectively. The many interactions possible with a compound library based on virtual hits compensates for the inherent fuzziness of any prediction tool. Examples have been described where the 2-D structure of a... 

Although combinatorial chemistry and HTS have offered medicinal chemists a much broader range of possibilities for lead discovery and optimization, the number of chemical compounds that can be reasonably synthesized, which is sometimes called virtual chemistry space , is stiU far beyond today s capability of chemical synthesis and biological assay. Therefore, medicinal chemists continue to face the same problem as before which compounds should be chosen for the next round of synthesis and testing For chemoinformaticians, the task is to develop and utilize various computer programs to evaluate a very large number of chemical compounds and recommend the most promising ones for bench medicinal chemists. This process can be called virtual... 

Other terms have been employed for this general concept, including self-assembled combinatorial libraries, constitutional dynamic chemistry, and virtual combinatorial libraries . Dynamic combinatorial chemistry and dynamic combinatorial library seem to have found the broadest usage, while virtual combinatorial library is perhaps best reserved for conditions under which library members form at concentrations below detection limits in the absence of target (e.g.. Reference 81). 

Xue, L. and Bajorath, J. (2000) Molecular descriptors in chemoinformatics, computational combinatorial chemistry, and virtual screening. Combin. Chem. High Throughput Screen. 3, 363-372. 

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... 

Key words QSAR, Free-Wilson, MLR, virtual libraries, combinatorial chemistry, protein kinase,... 

As combinatorial chemistry has been fully integrated into the modern drug discovery process, more computational search methodologies against large virtual combinatorial compound spaces have been steadily developed in recent years (11-16). A detailed summary and comparison of those published methods are reported in the Section 5 and in Table 13.6. A good review on this subject could also be found in the publication by Boehm and coworkers (16). 

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