title: Molecular similarity analysis uncovers heterogeneous structure-activity relationships and variable activity landscapes.
abstract: We systematically compare X-ray structures of inhibitor complexes of four well-known enzymes and correlate two- and three-dimensional (2D and 3D) similarity of inhibitors with their potency. The analysis reveals the presence of unexpected systematic relationships between molecular similarity and potency. These findings explain why apparently inconsistent structure-activity relationships (SARs) can coexist in different targets, and they have general implications for compound screening and optimization. The results suggest that (1) even for active sites with significant binding constraints, there is a high probability that structurally diverse ligands with similar activity can be identified, (2) different types of SARs are not mutually exclusive, and (3) the chemical nature of ligands is of comparable importance for SARs as the features of active sites. These insights aid in the understanding of target-specific SARs and their intrinsic degree of variability.
authors.affiliation: Department of Life Science Informatics, B-IT, Rheinische Friedrich-Wilhelms-Universität, Dahlmannstrasse 2, D-53113 Bonn, Germany.
authors.forename: Lisa
authors.initials: L
authors.lastname: Peltason
authors.forename: Jürgen
authors.initials: J
authors.lastname: Bajorath
mesh_terms: D000465:Algorithms; D001665:Binding Sites; D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry; D002256:Carbonic Anhydrases / Q000737:chemistry; D003460:Crystallization; D030562:Databases, Protein; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D015951:Factor Xa / Q000737:chemistry; D008958:Models, Molecular; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D012259:Ribonuclease, Pancreatic / Q000037:antagonists & inhibitors / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D002257:Carbonic Anhydrase Inhibitors; D004791:Enzyme Inhibitors; D012259:Ribonuclease, Pancreatic; D010196:Pancreatic Elastase; D015951:Factor Xa; D002256:Carbonic Anhydrases