Compound Collections - Diversity

Many corporate screening collections may inadvertently contain two or more samples of the same compound, for example, from different synthetic batches. Examining the results from a large number of such replicate samples can provide a useful way to assess the upper limit of variability in the primary assay. This represents an upper limit because other factors such as compound degradation can account for an unknown amount of the observed variability. Such replicate samples can also be filtered out if desired. 

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Centerpieces of combinatorial concepts include the synthesis of compound libraries instead of the preparation of single target compounds. Library synthesis is supplemented by approaches to optimize the diversity of a compound collection (diversity-oriented synthesis) and by efforts to create powerful interfaces between combinatorial synthesis and bioassays. 

The potential sources of the compounds that are evaluated in a hit triage process are described in other chapters in this volume. These sources may include a high throughput screen (HTS) of a diverse compound collection, a targeted screen of... 

The first application of a computational method to select structurally diverse compounds for purchase started in 1992 at the Upjohn Company, which predated the formation of Pharmacia Upjohn by about three years. The basic approach selected compounds using a method based upon maximum dissimilarity and was implemented using SAS software [11]. This later evolved into the program Dfragall, which was written in C and is described in Section 13.6.3. Basically, a set of compounds that is maximally dissimilar from the corporate compound collection is chosen from the set of available vendor compounds. Early versions of the process relied solely on diversity-based metrics but it was found that many nondrug like compounds were identified. As a result, structural exclusion criteria were developed to eliminate compounds that were considered unsuitable for... 

As the nature of chemistry space depends upon the way in which compounds are represented, an absolute or universal chemistry space does not exist. Thus, any procedure that utilizes chemistry space may be subject to considerable uncertainty, and the results obtained in different chemistry spaces are likely to differ, sometimes in quite significant ways. This rather daunting circumstance has necessitated the use of practical, heuristic approaches that, while imperfect, have nevertheless performed in a reasonably satisfactory manner over the last three years. During this period about 120000 diverse, quality compounds have been added to our corporate compound collection. This does not include the many compounds obtained from combinatorially derived libraries and special target-directed (e.g., kinase) libraries. 

DVS offers a cell-based method for assessing the diversity of compound collections. The orthogonal chemistry space is partitioned into cells, and the occupancy of each cell is easily determined. Diversity voids , or unoccupied regions of chemistry space, are identified with unoccupied cells or cells of low occupancy, which are also easily recognized. Enhancing diversity of a compound collection thus consists of filling empty and low-occupancy cells (see Figure 13.5). 

Fig. 10.6 Concept of multitarget affinity specificity screening (MASS). Macromolecular targets (typically structured RNA constructs or proteins) in nondenaturing buffers are mixed in solution with a collection of potential ligands derived from natural product fractions, combinatorial libraries, or other diverse compound collections. The...

Derivatization of functional groups in a natural-product scaffold can also be effectively performed on the solid-phase. An example of this is the synthesis of a small compound collection (27-compounds) based on the tetrahydroquinoline scaffold. A chiral tetrahydroquinoline scaffold was synthesized in solution from 5-hydroxy-2-nitrobenzaldehyde (Scheme 4). The synthesis involved a key asymmetric aminohydroxylation step. This building block was anchored to the solid support with a Wang linker and diversity was introduced by selective deprotection and derivatization of the protected hydroxyl and amino substituents. 

As mentioned above, it is now common for pharmaceutical companies to select a diverse set of compounds for screening that represent the available compounds (either internal or commercially available). Yet, this is not so for compound collections that have grown as sets of compounds, have been synthesized, or have been acquired for particular projects. This is an important reason why many examples of data-mining techniques when applied to the NCI dataset work so well and may help explain why such methods often do not perform as well against different HTS datasets (22). 

One approach to screening subsets of available compounds is to screen sets of compounds that, although not representative of the molecular diversity of the available compound collection, do contain as much structure activity relationship information as possible. An example of this was the Informer Library strategy proposed by CombiChem (which was eventually purchased by DuPont Pharmaceuticals in 1999) (23). Unfortunately, there have been no published applications of this screening strategy that assess its success or failure. 

As mentioned above, the MP approach was originally designed to aid in diversity evaluation of large compound collections and selection of representative subsets (see Note 6). In this case, an MP grid with a predefined number of par-... 

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). 

Selection of the reagents was based on the Pfizer internal compound collection which allowed speedy acquisition of any selected compound. A set of primary amines, secondary amines, and carboxylic acids which were not commercially available were chosen for consideration. These acids and amines were designed by medicinal chemists via a Pfizer internal screening file enrichment effort to be novel and diverse, and more importantly, were not part of any existing Pfizer fragment collection. The MW... 

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