J Chem Inf Model - Single R-Group Polymorphisms (SRPs) and R-cliffs: an intuitive framework for analyzing and visualizing activity cliffs in a single analog series.

Tópicos

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Resumo

We introduce Single R-Group Polymorphisms (SRPs, pronounced 'sharps'), an intuitive framework for analyzing substituent effects and activity cliffs in a single congeneric series. A SRP is a pair of compounds that differ only in a single R-group position. Because the same substituent pair may occur in multiple SRPs in the series (i.e., with different combinations of substituents at the other R-group positions), SRP analysis makes it easy to identify systematic substituent effects and activity cliffs at each point of variation (R-cliffs). SRPs can be visualized as a symmetric heatmap where each cell represents a particular pair of substituents color-coded by the average difference in activity between the compounds that contain that particular SRP. SRP maps offer several advantages over existing techniques for visualizing activity cliffs: 1) the chemical structures of all the substituents are displayed simultaneously on a single map, thus directly engaging the pattern recognition abilities of the medicinal chemist; 2) it is based on R-group decomposition, a natural paradigm for generating and rationalizing SAR; 3) it uses a heatmap representation that makes it easy to identify systematic trends in the data; 4) it generalizes the concept of activity cliffs beyond similarity by allowing the analyst to sort the substituents according to any property of interest or place them manually in any desired order.

Resumo Limpo

introduc singl rgroup polymorph srps pronounc sharp intuit framework analyz substitu effect activ cliff singl congener seri srp pair compound differ singl rgroup posit substitu pair may occur multipl srps seri ie differ combin substitu rgroup posit srp analysi make easi identifi systemat substitu effect activ cliff point variat rcliff srps can visual symmetr heatmap cell repres particular pair substitu colorcod averag differ activ compound contain particular srp srp map offer sever advantag exist techniqu visual activ cliff chemic structur substitu display simultan singl map thus direct engag pattern recognit abil medicin chemist base rgroup decomposit natur paradigm generat ration sar use heatmap represent make easi identifi systemat trend data general concept activ cliff beyond similar allow analyst sort substitu accord properti interest place manual desir order

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