Compound collections

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. 

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. 

The previous sections have summarized the basic techniques available for searching chemical databases for specific types of query. Another important database application is compound selection, the ability to select a subset of a database for submission to a biological testing program. The selection procedure can be applied to in-house databases, to externally available compound collections, or to virtual libraries, that is, sets of compounds that could potentially be synthesized. 

Several of the software tools used most frequently today include Beilstein Crossfire (information at www.mdli.com) and SciFinder from the Chemical Abstracts Service (www.cas.org/scifinder/) for structure-based reaction searches. Reagent availability information is often searched with MDL s ACD and CAS s SciFinder. Special compound collections and contract services offered by new companies such as ChemNavigator (www.chemnavigator.com)... 

The same template as for compound 71 was used by Peukert et al. for a 2D similarity search in the Aventis in-house compound collection [144]. 75 Compounds with a similarity index >0.80 were biologically tested. The moderately active l-carboxy,8-sulfonamido-naphthalene (IC50 = 9.5pM), with insufficient chemical stability, was the starting point for the design of substi-... 

An improved 3D pharmacophore, considering all results obtained so far, and a new 3D search in the Aventis compound collection with the program... 

Molecules in real solvents can exist in one or more tautomeric forms. The use of different tautomers in calculations can lead to significant variation in the estimated log P values (Pig. 15.1). Accurate prediction of the dominant tautomer requires ah initio calculahons. Due to speed limitations such calculations are not feasible for virtual screening and prediction of large compound collections. Moreover, the interpretation of the results can also be difficult, for example, the lacton-lactim (Pig. 15. IB) is the stable form of maleic hydrazide in the gas phase but the difference between this and the dilacton form (Pig. 15.1C and D) disappears in solution... 

Muresan, S., Sadowski,). In-house likeness comparison of large compound collections using artificial neural networks. f Chem. Inf Model. 2005, 45, 888-893. 

Generally, performance of a method is often judged in one of two ways. The first is the enrichment factor, enrichment for short, which is the ratio of the cumulative number of actives in the top N% of the total number in the dataset to random retrieval rate. Many early studies focused on the enrichment obtained when the top 10% of the dataset was screened. However, this is operationally unrealistic if compound collections exceed 100,000 compounds, which is common in mid- to large-sized companies. A more realistic test is the enrichment obtained in the top... 

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... 

Detection in CC may be visually for coloured compounds. Different methods can be used to monitor colourless compounds (collecting fractions addition of an inorganic phosphor to the column adsorbent). The detector choice is quite limited, with UV, RI and molecular fluorescence (F) emission being the most popular. A fluorescent column adsorbent is extremely... 

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