title: Fragment-based similarity searching with infinite color space.
abstract: Fragment-based searching and abstract representation of molecular features through reduced graphs have separately been used for virtual screening. Here, we combine these two approaches and apply the algorithm RedFrag to virtual screens retrospectively and prospectively. It uses a new type of reduced graph that does not suffer from information loss during its construction and bypasses the necessity of feature definitions. Built upon chemical epitopes resulting from molecule fragmentation, the reduced graph embodies physico-chemical and 2D-structural properties of a molecule. Reduced graphs are compared with a continuous-similarity-distance-driven maximal common subgraph algorithm, which calculates similarity at the fragmental and topological levels. The performance of the algorithm is evaluated by retrieval experiments utilizing precompiled validation sets. By predicting and experimentally testing ligands for endothiapepsin, a challenging model protease, the method is assessed in a prospective setting. Here, we identified five novel ligands with affinities as low as 2.08 μM.
authors.affiliation: Department of Pharmaceutical Chemistry, Philipps-University, Marbacher Weg 6, Marburg, 35032, Germany.
authors.forename: Jakub
authors.initials: J
authors.lastname: Gunera
authors.affiliation: Department of Pharmaceutical Chemistry, Philipps-University, Marbacher Weg 6, Marburg, 35032, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Kolb
mesh_terms: D000465:Algorithms; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D003116:Color; D003196:Computer Graphics; D017076:Computer-Aided Design; D062313:Databases, Pharmaceutical; D015195:Drug Design; D008024:Ligands; D015394:Molecular Structure
chemical_list: D008024:Ligands; D016282:Aspartic Acid Endopeptidases; C042466:Endothia aspartic proteinase
keywords: endothiapepsin; fragment-based similarity; molecule fragmentation; reduced graphs; scaffold hopping