title: From activity cliffs to activity ridges: informative data structures for SAR analysis.
abstract: The extraction of SAR information from structurally diverse compound data sets is a challenging task. One of the focal points of systematic SAR analysis is the search for activity cliffs, that is, structurally similar compounds having large potency differences, from which SAR determinants can be deduced. The assessment of SAR information is usually based on pairwise similarity and potency comparisons of data set compounds. As a consequence, activity cliffs are mostly evaluated at a compound pair level. Here, we present an extension of the activity cliff concept by introducing "activity ridges" that are formed by overlapping "combinatorial" activity cliffs between participating compounds, giving rise to ridge-like structures in activity landscapes. Activity ridges are rich in SAR information. In a systematic analysis of 242 compound data sets, we have identified well-defined activity ridges in 71 different sets. In addition, an information-theoretic approach has been devised to characterize the structural composition of activity ridges. Taken together, our results show that activity ridges frequently occur in sets of active compounds and that different categories of ridges can be distinguished on the basis of their structural content. The computational identification of activity ridges provides access to compound subsets having high priority for SAR analysis.
authors.affiliation: Department of Life Science Informatics, B-IT, LIMES Program Unit Chemical Biology and Medicinal Chemistry, Rheinische Friedrich-Wilhelms-Universität, Bonn, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Vogt
authors.forename: Yun
authors.initials: Y
authors.lastname: Huang
authors.forename: Jürgen
authors.initials: J
authors.lastname: Bajorath
mesh_terms: D000465:Algorithms; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D003198:Computer Simulation; D057225:Data Mining; D016208:Databases, Factual; D015195:Drug Design; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D008956:Models, Chemical; D015394:Molecular Structure; D004364:Pharmaceutical Preparations / Q000032:analysis* / Q000737:chemistry; D012984:Software; D013329:Structure-Activity Relationship
chemical_list: D004364:Pharmaceutical Preparations