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J Chem Inf Model. 2013 Jun 24;53(6):1475-85. doi: 10.1021/ci400192y. Epub 2013 Jun 7.

Rapid scanning structure-activity relationships in combinatorial data sets: identification of activity switches.

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1
Torrey Pines Institute for Molecular Studies, Port St. Lucie, Florida 34987, USA. jmedina@tpims.org

Abstract

We present a general approach to describe the structure-activity relationships (SAR) of combinatorial data sets with activity for two biological endpoints with emphasis on the rapid identification of substitutions that have a large impact on activity and selectivity. The approach uses dual-activity difference (DAD) maps that represent a visual and quantitative analysis of all pairwise comparisons of one, two, or more substitutions around a molecular template. Scanning the SAR of data sets using DAD maps allows the visual and quantitative identification of activity switches defined as specific substitutions that have an opposite effect on the activity of the compounds against two targets. The approach also rapidly identifies single- and double-target R-cliffs, i.e., compounds where a single or double substitution around the central scaffold dramatically modifies the activity for one or two targets, respectively. The approach introduced in this report can be applied to any analogue series with two biological activity endpoints. To illustrate the approach, we discuss the SAR of 106 pyrrolidine bis-diketopiperazines tested against two formylpeptide receptors obtained from positional scanning deconvolution methods of mixture-based libraries.

PMID:
23705689
PMCID:
PMC3715655
DOI:
10.1021/ci400192y
[Indexed for MEDLINE]
Free PMC Article
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