title: Single R-Group Polymorphisms (SRPs) and R-cliffs: an intuitive framework for analyzing and visualizing activity cliffs in a single analog series.
abstract: 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.
authors.affiliation: Informatics, Johnson & Johnson Pharmaceutical Research & Development, L.L.C. , Welsh & McKean Roads, Spring House, Pennsylvania 19477, United States.
authors.forename: Dimitris K
authors.initials: DK
authors.lastname: Agrafiotis
authors.forename: John J M
authors.initials: JJ
authors.lastname: Wiener
authors.forename: Andrew
authors.initials: A
authors.lastname: Skalkin
authors.forename: Jeremy
authors.initials: J
authors.lastname: Kolpak
mesh_terms: D002403:Cathepsins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D003196:Computer Graphics; D055808:Drug Discovery; D008024:Ligands; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000737:chemistry*; D012984:Software; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D011480:Protease Inhibitors; D002403:Cathepsins; C028217:cathepsin S