Individual compound libraries

Enantioresolution in capillary electrophoresis (CE) is typically achieved with the help of chiral additives dissolved in the background electrolyte. A number of low as well as high molecular weight compounds such as proteins, antibiotics, crown ethers, and cyclodextrins have already been tested and optimized. Since the mechanism of retention and resolution remains ambiguous, the selection of an additive best suited for the specific separation relies on the one-at-a-time testing of each individual compound, a tedious process at best. Obviously, the use of a mixed library of chiral additives combined with an efficient deconvolution strategy has the potential to accelerate this selection. 

Combinatorial Chemistry. Figure 2 Chemical libraries are prepared either by parallel synthesis or by the split-and-recombine method. In the latter case, coupling m building blocks in m separated reaction flasks through n synthetic cycles on a beaded polymer carrier generates a combinatorial library with nf individual compounds and one compound per bead. 

A compound library is a compound collection. The compound libraries of large pharmaceutical and screening companies can exceed 1 million samples. Libraries are synthesized and stored as either individual samples or as combinations. 

In research, many quantitative and graphical methods are used in selecting between individual compounds, either as potential library of collection members or in filtering hits. Multicriteria approaches to library design typically seek to balance diversity and likelihood of favorable properties [16]. In early screening, the rules for choices between hits are part of a research process typically applied to diverse projects, whereas at the end of the discovery process compound choice commits to starting a single development project. 

Whatever the analyser and the analytical conditions chosen, the spectrum obtained corresponds to the sum of the spectra of all the individual compounds present in the sample investigated. Spectra have thus to be cautiously interpreted using a set of reference data from single commercial or synthesised compounds, reference raw and aged natural substances and mass spectral libraries. 

The synthesis of libraries of structurally defined compounds can potentially be achieved either by split-mix synthesis or by parallel synthesis of individual compounds. The synthesis requires a reliable methodology of oligosaccharide synthesis, where stereochemistry and regioselectivity have to be achieved unlike other library approaches. Development of synthetic methodologies that can provide access to any oligosaccharide structure is underway. 

As first practiced by Geysen and Houghton, the preparation of combinatorial libraries produced discrete compounds of known identity through a technique known as "spatial separation," which simply means that individual compounds in the library are produced discretely and are not mixtures. Such spatially addressable compound sets are produced in such a way as to keep separate the reaction flasks or resin beads containing the individual components of the library and perform bioassays on the discrete compounds, one at a time. Thus, if the "history" of the reaction conditions performed in each flask or on each solid support, the identity of the compounds produced is known, without resort to structure elucidation techniques. Initially, this technique, after typically an extensive reaction development stage, allowed the preparation of between 10 and 1000 discrete combinatorial products. 

In general, larger libraries, other than those of Pharmacopeia and Houghten, have tended to be in the range of 5000 to 15000 compounds, particularly if the enhre library was purified and stored as individual compounds. The same methods and algorithms as for diverse library design apply here. However, it now becomes possible... 

Several other approaches with the goal of simultaneous optimization of several criteria have been reported. One such approach is the generation of a library that is both focused and diverse via the dual fingerprint metric described by Bajorath [94], In this method, individual compounds are randomly generated and their similarity to a known inhibitor is evaluated by comparison of their minifingerprints [95] using the Tanimoto coefficient. Those molecules that are above a similarity threshold are then... 

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 . 

Even though we have seen that the solubility predictions are poor for individual compounds, there is still a question over whether such predictions could nevertheless be useful in library design. We believe that they can. Figure 15.5 shows that QMPRPIus gets the general trend correct it shows that the proportion of soluble compounds increases with an increase in the solubility predicted by QMPRPIus (where a soluble compound is defined to have intrinsic solubility greater than 10 M). 

There are approximately 2700 compounds per primary screening mixture, and the readout is in essence multiplexed the ligands are individually ionized and identified in the mass spectrometer according to their exact mass positions. The readout, however, does not unambiguously identify compounds, as multiple compounds in a single mixture may have the same mass, i.e., a particular peak may correspond to as many as 31 compounds with closely related masses. The protein excess over individual compounds coupled with the rarity of potent ligands within a randomly assembled library minimizes competition between ligands for... 

Electronic databases of the mass spectral fragmentation patterns of known molecules can be rapidly searched by computer. The pattern and intensity of fragments in the mass spectrum is characteristic of an individual compound so comparison of the experimental mass spectrum of a compound with those in a library can be used to positively identify it, if its spectrum has been recorded previously. 

It is now common to couple an instrument for separating a mixture of organic compounds e.g. using gas chromatography (GC) or high performance liquid chromatography (HPLC), directly to the input of a mass spectrometer. In this way, as each individual compound is separated from the mixture, its mass spectrum can be recorded and compared automatically with the library of known compounds and identified immediately if it is a known compound. 

As synthetic steps, the Michael additions of nitrogen nucleophiles were followed by nucleophilic substitutions of the chlorine atom with a primary amine and, finally, alkylations of the then secondary amino group with various alkyl bromides were performed just as previously developed for the chloro ester 1-Me in solution (see, e.g. Schemes 25,27,36 etc.). With differently substituted pyra-zoles as Michael addends, different primary amines and alkyl bromides, combinatorial libraries consisting of 8, 24 and 84 compounds were thus successfully prepared in ca. 60% yield and proved by the LC-MS technique to contain all the individual compounds in about equal amounts (Scheme 80) [127]. 

One or more lead molecules may be used as a focusing target. Similarity metrics include Daylight fingerprint Tanimoto similarity. The penalty score for each compound in the library is defined as the distance between it and the most similar lead molecule. The penalty score for the library is the average of the individual compound penalty scores. QSAR predictions and docking scores can also be used in this term. 

There are three major sources for a typical corporate compound collection project-specific compounds accumulated over a long period of time through medicinal chemistry efforts for various therapeutic projects, individual compounds from commercial sources, and compounds from combinatorial chemistry. In practice, compound collections are often divided into subsets, for example, the diverse subsets for general HTS and target-focused subsets (such as kinase libraries or GPCR libraries). For library design, diversity and similarity are generally built into the libraries of compounds to be synthesized and/or purchased (73). 

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