title: Analysis of a high-throughput screening data set using potency-scaled molecular similarity algorithms.
abstract: Molecular similarity methods for ligand-based virtual screening (VS) generally do not take compound potency as a variable or search parameter into account. We have incorporated a logarithmic potency scaling function into two conceptually distinct VS algorithms to account for relative compound potency during search calculations. A high-throughput screening (HTS) data set containing cathepsin B inhibitors was analyzed to evaluate the effects of potency scaling. Sets of template compounds were randomly selected from the HTS data and used to search for hits having varying potency levels in the presence or absence of potency scaling. Enrichment of potent compounds in small subsets of the HTS data set was observed as a consequence of potency scaling. In part, observed enrichments could be rationalized as a result of recentering chemical reference space on a subspace populated by potent compounds. Our findings suggest that VS calculations using multiple reference compounds can be directed toward the preferential detection of potent database hits by scaling compound contributions according to potency differences.
authors.affiliation: Department of Life Science Informatics, B-IT, Rheinische Friedrich-Wilhelms-Universität, Dahlmannstrasse 2, D-53113 Bonn, Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Vogt
authors.forename: Jürgen
authors.initials: J
authors.lastname: Bajorath
mesh_terms: D000465:Algorithms; D002401:Cathepsin B / Q000037:antagonists & inhibitors / Q000378:metabolism; D019295:Computational Biology / Q000379:methods*; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000032:analysis / Q000737:chemistry; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D002401:Cathepsin B