Abstract
In the past 20 years, synthetic combinatorial methods have fundamentally advanced the ability to synthesize and screen large numbers of compounds for drug discovery and basic research. Mixture-based libraries and positional scanning deconvolution combine two approaches for the rapid identification of specific scaffolds and active ligands. Here we present a quantitative assessment of the screening of 32 positional scanning libraries in the identification of highly specific and selective ligands for two formylpeptide receptors. We also compare and contrast two mixture-based library approaches using a mathematical model to facilitate the selection of active scaffolds and libraries to be pursued for further evaluation. The flexibility demonstrated in the differently formatted mixture-based libraries allows for their screening in a wide range of assays.
Highlights
Mixture-based combinatorial libraries, reviewed in [1,2,3], are an efficient and effective way to explore large, dense areas of the chemical space in an exponentially smaller number of samples In a positional scanning mixture-based combinatorial library, mixtures are systematically arranged and tested in order to determine those most likely to contain active compounds [4,5]
An equimolar combination of all of the mixtures in one position of a positional scanning library will result in an equimolar mixture of all the compounds within that library, i.e., the scaffold ranking mixture associated with that library
With the side-by-side data presented in this study, we have shown for the first time that scaffold ranking is sufficient for accurately demonstrating the overall activity of a library, with each library presenting essentially the same activity levels in its scaffold ranking format as in its full positional scanning format
Summary
Mixture-based combinatorial libraries, reviewed in [1,2,3], are an efficient and effective way to explore large, dense areas of the chemical space in an exponentially smaller number of samples In a positional scanning mixture-based combinatorial library, mixtures are systematically arranged and tested in order to determine those most likely to contain active compounds [4,5]. The flexibility of these two screening formats of mixture-based libraries represents a clear advantage for the rapid identification of active lead compounds The use of both positional scanning libraries and scaffold ranking have been previously reported [3,8,9,10,11], but there has heretofore never been a comprehensive study comparing scaffold ranking results to positional scanning results across a large number of libraries. The results presented here demonstrate that the scaffold ranking library samples lead to effective selection of active positional scanning libraries; determining the relative activities of the libraries as the first step of a screening campaign does not require the use of the complete collection of positional scanning libraries This strategy greatly reduces the time and resources required by testing a fraction of the samples with equivalent accuracy. It will be shown that use of the complete collection of positional scanning libraries provides screening data that offers important information, beyond activity alone, which increases the likelihood of the successful deconvolution of a library
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