J Chem Inf Model - Rapid scanning structure-activity relationships in combinatorial data sets: identification of activity switches.

Tópicos

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Resumo

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.

Resumo Limpo

present general approach describ structureact relationship sar combinatori data set activ two biolog endpoint emphasi rapid identif substitut larg impact activ select approach use dualact differ dad map repres visual quantit analysi pairwis comparison one two substitut around molecular templat scan sar data set use dad map allow visual quantit identif activ switch defin specif substitut opposit effect activ compound two target approach also rapid identifi singl doubletarget rcliff ie compound singl doubl substitut around central scaffold dramat modifi activ one two target respect approach introduc report can appli analogu seri two biolog activ endpoint illustr approach discuss sar pyrrolidin bisdiketopiperazin test two formylpeptid receptor obtain posit scan deconvolut method mixturebas librari

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