Combinatorial virtual

Reactor can be set up to carry out simple sequential enumeration, combinatorial enumeration, generating combinatorial virtual synthetic libraries. Users also have the option to exclude imwanted products from the enumeration results manually, restricting the outcome of the reaction enumeration process to the desired main products only. Reactor supports the generation of product or reaction libraries in a large variety of different output formats. 

It is remarkable that only two descriptors were needed in this method. However, this equation is mostly only of historical interest as it is of little use in modem dmg and combinatorial library design because it requires a knowledge of the compound s experimental melting point which is not available for virtual compounds. Several methods exist for estimating log P [1-14], but only a few inroads have been made into the estimation of melting points. The melting point is a key index of the cohesive interactions in the solid and is still difficult to estimate. 

HTS data as well as virtual screening can guide and direct the design of combinatorial libraries. A genetic algorithm (GA) can be applied to the generation of combinatorial libraries [18. The number of compounds accessible by combinatorial synthesis often exceeds the number of compounds which can be syiithcsii ed... 

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. 

The term enumeration when applied to a combinatorial library refers to the process by which the cormection tables for the product structures in a real or virtual library are produced. It should be noted that a single compound can be considered as a library of one and so enumeration can equally well be applied in this case. However, whereas it is considered reasonable for a chemist to draw the structure of a single compoimd manually (which may have taken days, if not months or years, to synthesise), it is clearly not practical to do so even for small combinatorial libraries. Hence the need for automated tools to perform this procedure. 

Another example for the use of hydrogen as reductant is observed in the reduction of imine [5b]. New imine reductase activity has been discovered in the anaerobic bacterium Acetobacterium woodii by screening a dynamic combinatorial library of virtual imine substrates, using a biphasic water-tetradecane solvent system. 

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. 

Sprous DG, Lowis DR, Leonard JM, Heritage T, Burkett SN, Baker DS, Clark RD. OptiDock virtual HTS of combinatorial libraries by efficient sampling of binding modes in product space. J Comb Chem 2004 6 530-9. 

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

Closely related to the use of PSA in virtual screening is its application in the design of combinatorial libraries with optimal properties. These applications are reviewed further in Refs. [46, 47], for example. 

As stated above, an advantage of virtual screening is that any compound, real or virtual, can be screened and the user is not restricted to those compounds available in corporate or external collections. The technology can also be used to screen proposed libraries and even select monomers for a combinatorial library based on 3D fit to the target structure. 

The next vague of tools will be around computational or in silico ADME approaches. These will allow to include ADME into the design of combinatorial libraries, the evaluation of virtual libraries, as well as in selecting the most promising compounds to go through a battery of in vitro screens, possibly even replacing some of these experimental screens. Several of these computational tools are currently under development as will be discussed in this volume. 

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

Unlike OS, solid-phase methods will virtually always be invented for application in combinatorial organic synthesis. To meet these specific needs, SPOS procedures will focus not on multistep reactions leading to a desired final compound but rather on a single type of synthetic transformation accomplished on... 

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