Candidate library

Spectral searches using a library of reference spectra can be a useful tool in identification. Search algorithms have improved over the years and now use the concept of artificial intelligence. Several software packages can be used to conduct searches in spectral libraries in which the main peaks of known compounds are encoded. The compounds offering the best matches are retained as potential candidates. Library searches involve three stages ... 

Figure 6.10 Procedure for bioaffinity screening of combinatorial drug candidates libraries with two cycles of iterative size exclusion chromatography, using spin columns to separate the receptor and receptor-binder complexes from unbound ligands. (Reprinted with permission from Davis et al., 1999. Copyright 1999 American Chemical Society.)...

The RBPB algorithm of Pearlman and Smith, described above (Section 4,2), considers all possible candidate libraries, which satisfy the user s constraints regarding economy. These include min/max range constraints regarding library size (e.g., number of AB products) and the number of each type of reactant (e.g., number of A s and number of B s). These also include specification of the minimal unit dimensions (MUDs), which define the smallest combinatorial array that the user is willing to address on the robotictable. Each candidate library corresponds to a different way of, at least conceptually, arranging the required... 

Once candidate library members have been chosen, they must be validated by experiment. For each library member, the chemical structure is verified, the purity of the sample determined, and aqueous solubility measured. In addition, the fragments should be tested for their potential to aggregate at the high screening concentrations used for fragment-based NMR screening [51]. DMSO-d6 stock solutions of the library must be plated and stored in a way that minimizes freeze/... 

Comparison of a measured spectrum with a candidate library spectrum is feasible by these different principles ... 

In the simplest case, the unknown spectrum is compared with the candidate library spectrum by an AND connective (cf. Table 1.2). 

Figure 7.8 Comparison of an unknown spectrum (A) with a candidate library spectrum (B) by the exclusive OR connective (XOR).

Fig. 5. The degree of overlap between a combinatorial library and a reference collection can be calculated as the fraction of compounds in the candidate library that lie in cells also occupied by one or more compounds from the reference set. Here we show degree of overlap with the ArQule compound repository for the optimized library of 2000 compounds vs the average of three libraries formed by randomly selecting reagents (as in Fig. 4). In this case, optimization reduces the redundancy relative to the reference collection by about 1/3.

The candidate library was dien screened against the CLASS e q)ert system. We found the CLASS filter was useful in identifying unattractive iiqtuts that would have been removed during the scientist reviews. For exanq>le, molecules with reactive groups or long aU rl chains received low scores and subsequently were removed from the candidate library. We made substitutions for these iiq>uts and screened using CLASS until all molecules passed . 

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