title: Structure-activity relationship anatomy by network-like similarity graphs and local structure-activity relationship indices.
abstract: The study of structure-activity relationships (SARs) of small molecules is of fundamental importance in medicinal chemistry and drug design. Here, we introduce an approach that combines the analysis of similarity-based molecular networks and SAR index distributions to identify multiple SAR components present within sets of active compounds. Different compound classes produce molecular networks of distinct topology. Subsets of compounds related by different local SARs are often organized in small communities in networks annotated with potency information. Many local SAR communities are not isolated but connected by chemical bridges, i.e., similar molecules occurring in different local SAR contexts. The analysis makes it possible to relate local and global SAR features to each other and identify key compounds that are major determinants of SAR characteristics. In many instances, such compounds represent start and end points of chemical optimization pathways and aid in the selection of other candidates from their communities.
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: Mathias
authors.initials: M
authors.lastname: Wawer
authors.forename: Lisa
authors.initials: L
authors.lastname: Peltason
authors.forename: Nils
authors.initials: N
authors.lastname: Weskamp
authors.forename: Andreas
authors.initials: A
authors.lastname: Teckentrup
authors.forename: Jürgen
authors.initials: J
authors.lastname: Bajorath
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors / Q000737:chemistry; D051546:Cyclooxygenase 2 / Q000737:chemistry / Q000187:drug effects; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D015951:Factor Xa / Q000737:chemistry; D065427:Factor Xa Inhibitors; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000037:antagonists & inhibitors / Q000737:chemistry; D008024:Ligands; D008084:Lipoxygenase / Q000737:chemistry / Q000187:drug effects; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors / Q000737:chemistry
chemical_list: D004791:Enzyme Inhibitors; D065427:Factor Xa Inhibitors; D008024:Ligands; D008084:Lipoxygenase; D051546:Cyclooxygenase 2; D019883:Alkyl and Aryl Transferases; C064911:p21(ras) farnesyl-protein transferase; D013186:Farnesyl-Diphosphate Farnesyltransferase; D013917:Thrombin; D015951:Factor Xa