Directed libraries

Rather than perform individual syntheses of all possible combinations of these nonpeptide units, members of each ring type or scaffold family were pooled in equimolar amounts prior to incorporation into the sequence DArg-Arg-X-Y-Arg. Since each individual member of a given pool was constructed on a similar carbocyclic scaffold, the chemical environment of the N-terminal amino group and C-terminal carboxylate groups were expected to follow similar kinetic and thermodynamic controls during the attachment of the nonpeptide residue to the growing peptide chain. The use of these smaller, directed libraries made it readily practical to obtain HPLC and mass spectral data for each and therefore confirm the composition of the library. 

A variety of unfunctionalized secondary alcohols, including saturated and unsaturated carbinols, are resolved by catalyst 25 with moderate to high selectivi-ties (fcrei=4 to >50, see Scheme 5) [25]. Octapeptide 25 was discovered by screening a split-pool library of peptide catalyst candidates for acylation of 1-phe-nylethanol (3), using a reactivity-based fluorescence screen [26], followed by structure optimization with directed libraries. While substrates with increased steric bulk about the alcohol are resolved with highest selectivities, even 2-butanol is resolved with modest selectivity (fcrei=4). Peptide-based catalysts have also been applied to the resolution of tertiary alcohols, a relatively unexplored area of nonenzymatic asymmetric acylation catalysis [27-29], By using a fluores-... 

One of the difficulties with this type of approach is that the quality of the results depends directly on the quality of the initial pharmacophore model, which can sometimes prove challenging. A particular hazard is that active compounds can have different binding modes, even in a closely related series of inhibitors. This algorithm partially addresses that problem, since it does not take as a fundamental assumption that all molecules bind in the same orientation, however further tools to identify alternative binding modes would be helpful. Overall it shows potential to be a powerful tool to direct library design. 

To evaluate the results of the directed library approach, a purely diverse library of 1000 compounds was also generated as a control. The overall results are shown in figure 16, comparing the number of compounds found in the directed library to the number of compounds found in diversity alone. Not only did the directed approach yield more hits, but also the ratio of directed/diverse hits increased as the potency increased (going from roughly twice as many to 7 times as many hits. The most potent compound had a Kj of 73nM for the directed approach. 

The diversity clustering analysis that was used to choose the final components of the directed library proved useful to design a second generation library quickly. We re-examined the clusters of the top scoring components, and generated a small library of 39 compounds from other components in those clusters. These are components that combiBUILD predicted would bind well, and which were similar to compounds that had already been shown experimentally to bind well. Almost all (92%) had IC50 better than lpM, and 18% were nanomolar inhibitors, the best with a Ki of 9nM. 

An Example On-Bead Screening and Structure Determination of Positives from SH3 Domain-Directed Libraries... 

Subramanian, T., Wang, Z., Troutman, J.M., Andres, D.A., and Spiehnann, H.P. (2005). Directed library of anilinogeranyl analogues of farnesyl diphosphate via mixed solid- and solution-phase synthesis. Org Lett 7 2109-2112. 

A directed library lies midway between an initial exploration library and a final i iimizaiion libraiy in its size and overall diversity. 

Fig. 4,13 Illustration of the protein site-directed library design protocol of Eksterowicz and coworkers [149], Starting with the protein structure, a site map is generated from the active site. Pharmacophores are enumerated and used to define the space for library design. Compounds are then selected with the...

Figure 2.14 Computational enumeration as an approach to design kinase directed libraries. (Figure reproduced in part with permission from J. G. Kettle and R. A. Ward, J. Chem. Inf. Model., 2010, 50 (4), 526 (Table 2)).

Directed libraries (LB in Table 19.2) represent one of the immediate follow-up approaches when a hit has been obtained. Representing an extension of the former approach, a small family of compounds is assembled around the basic structural template afforded by the initial hit compound. Although the nature of these members is often dictated by what types of chemistry are allowed to be performed on the hit compound s template, ideally a systematic attempt is made to map... 

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