Arrays libraries

The concept of reducing the number of reaction vessels and exponentially increasing the number of synthesized compounds was brought to a next level of simplicity by the split-and-pool method of Furka et al.5 The split-and-pool method was independently applied by Lam et al.6 in a one-bead-one-compound concept for the combinatorial synthesis of large compound arrays (libraries) and by Houghten et al.7 for the iterative libraries. Now several millions peptides could be synthesized in a few days. In Furka s method the resin beads receiving the same amino acid were contained in one reaction vessel—identical to Frank s method—however, the beads were pooled and then split randomly before each combinatorial step. Thus the method is referred to as the random split-and-pool method to differentiate it from Frank s method in which each solid-phase particle was directed into a particular reaction vessel (the directed split-and-pool method). 

A follow-on concept to the one-bead-one-compound concept was recently published as a library of libraries , whereby the authors demonstrated, for peptides, the idea of one-bead-one-motif [83], For linear peptides, this method assumes that some positions are important for structure and some are important for contact with the target. The library construction is accomplished by combining elements of an iterative library with a parallel array library. The construction of the library breaks the structure down into positions defined as structural positions and motif (pharmacophore) positions. The structural positions are built with mixtures of building blocks and the motif positions are constructed through the divide, couple, and recombine procedure. The results reported showed that peptide binding motifs could be identified that reproduced known motifs. 

Combinatorial chemistry provides a means of synthesizing a vast array (libraries) of compounds in clean single pot reactions. The majority of combinatorial approaches utilize polymeric solid supports as a base onto which the compounds are synthesized. However, there are also approaches which utilize solution-based chemistries to generate combinatorial libraries. 

Spatial arraying has been used traditionally for the assaying of historic compound collections. As the identity of the molecule is correlated to position in the array, this approach carries the least challenge for stmctural assigmnent for active array positions. As an additional aspect to ease the implementation of arrayed libraries, arrayed libraries are commonly handled as solutions. As most biological assays are based on homogeneous test systems, providing the libraries in solution is the obvious... 

For routine diagnostics in which the number of probes to be tested is smaller than in a de novo interaction screen, arrayed libraries show the higher potential because of the simplified handling. Today, these libraries are produced by spotting the individual probes on microscope slides that can be read out in fluorescence microscope readers after assaying. Reddy et al. 

Rodriguez, M., Li, S. S., Harper,J. W., Sc Songyang, Z. (2004). An oriented peptide array library (OPAL) strategy to study protein-protein interactions. The Journal of Biological Chemistry, 279, 8802-8807. 

FIGURE 11.72 Sublibraries of the circumdatin family of natural products. (From Grieder, A. and Thomas, A.W., A concise building block approach to a diverse multi-arrayed library of the circumdatin family of natural products, Synthesis, 11, 1707, 2003.)... 

Synthesis results. The final design was mapped to an implementation in LSI Logic s LCAIOK Compacted Array library with a cycle time of 67 nanoseconds to sustain a IS MHz clock frequency. Implementation statistics include the number of registers, the area cost using library parameters, and the critical path delay in nanoseconds. As in the Ethernet co-processor design, we estimate the scheduling cost as the sum of the maximum offsets in the relative... 

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