Virtual combinatorial library products

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. 

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%]. 

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.

Product-based selection is much more computationally demanding than reagent-based selection. Typically, it requires the computational enumeration of the full virtual combinatorial library and calculation of the descriptors for all possible products, prior to the application of a subset selection method. Consider a three-component reaction with 100 reagents available at each substituent position and assume that the aim is to build a 10 x 10 x 10 combinatorial library. In reagent-based selection, this requires the calculation of descriptors for 300 compounds (100 + 100 + 100). In product-based design, however, the full library of 1 million compounds (100 x 100 x 100) must be enumerated and descriptors must be calculated for each product molecule. 

The size of a virtual library can be reduced by applying filters to eliminate reagents that are known to be undesirable [67]. However, in some cases, the virtual library may still be too large to allow full enumeration, and thus full product-based design is infeasible. (Although the need for full enumeration may not be necessary in the future, for example, Barnard et al. [82] have recently developed a method for the rapid calculation of descriptors for the products in a virtual combinatorial library that avoids the need for enumeration.)... 

Weber et al. [63] have developed a GA that optimizes actual biological response for compounds within a virtual combinatorial library. Each chromosome in the GA represents a single product compound of the reaction. The fitness func-... 

The macrocyles formed depend on the overall proportions of 1 and 2, the diamine chain length and the type of cation used as the template. Of importance is the fact that the imine formation is a reversible reaction. Expressed in the DCC sense, one can say that all products, the macrocycies and the nonrepresented oligomers and polymers, are in constant equilibrium, and that all the species represented in Fig. 22 constitute a virtual combinatorial library (VCL). From this library, the high proportion of a specific macrocycle can be obtained by the use of the appropriate conditions (type of metal template, relative proportion of reactants). 

There are at least two alternative ways in how virtual combinatorial libraries can be built reaction-scheme entries or product-only transformations. The first method requires a description of a reaction, a number of rules for how to convert the reagent structures into its synthon forms the combination of synthons will then result in product structures. The product-only method is based on a core structure with defined variation sites on which different substituents can be selected. In the example given in this chapter, a combination of both methods is used. First reagents are converted into synthons and in a subsequent step a core molecule is given with two variation sites where the synthons formed in the first step are selected as substituents to form the product structures. 

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. 

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. 

A general approach to limiting the space of virtual libraries of combinatorial reaction products consists of implementation of a series of special filtering procedures. 

Basis products (BPs) Exploits the redundancy of fragments in a combinatorial library and identifies a small subset of compounds (BPs) which represent the entire virtual library. BPs are docked, scored, and used for final library enumeration (85)... 

The approach taken to achieve these goals was to first select a set of novel reagents, then react these compounds with simple reagents to cap the reactive functionalities. Virtual products for the selected compounds were created and are then passed through an in silico filtering process. Finally, the filtered libraries were synthesized via combinatorial libraries. 

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