title: Development of a virtual screening method for identification of "frequent hitters" in compound libraries.
abstract: A computer-based method was developed for rapid and automatic identification of potential "frequent hitters". These compounds show up as hits in many different biological assays covering a wide range of targets. A scoring scheme was elaborated from substructure analysis, multivariate linear and nonlinear statistical methods applied to several sets of one and two-dimensional molecular descriptors. The final model is based on a three-layered neural network, yielding a predictive Matthews correlation coefficient of 0.81. This system was able to correctly classify 90% of the test set molecules in a 10-times cross-validation study. The method was applied to database filtering, yielding between 8% (compilation of trade drugs) and 35% (Available Chemicals Directory) potential frequent hitters. This filter will be a valuable tool for the prioritization of compounds from large databases, for compound purchase and biological testing, and for building new virtual libraries.
authors.affiliation: F. Hoffmann-La Roche AG, CH-4070 Basel, Switzerland.
authors.forename: Olivier
authors.initials: O
authors.lastname: Roche
authors.forename: Petra
authors.initials: P
authors.lastname: Schneider
authors.forename: Jochen
authors.initials: J
authors.lastname: Zuegge
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Guba
authors.forename: Manfred
authors.initials: M
authors.lastname: Kansy
authors.forename: Alexander
authors.initials: A
authors.lastname: Alanine
authors.forename: Konrad
authors.initials: K
authors.lastname: Bleicher
authors.forename: Franck
authors.initials: F
authors.lastname: Danel
authors.forename: Eva-Maria
authors.initials: EM
authors.lastname: Gutknecht
authors.forename: Mark
authors.initials: M
authors.lastname: Rogers-Evans
authors.forename: Werner
authors.initials: W
authors.lastname: Neidhart
authors.forename: Henri
authors.initials: H
authors.lastname: Stalder
authors.forename: Michael
authors.initials: M
authors.lastname: Dillon
authors.forename: Eric
authors.initials: E
authors.lastname: Sjögren
authors.forename: Nader
authors.initials: N
authors.lastname: Fotouhi
authors.forename: Paul
authors.initials: P
authors.lastname: Gillespie
authors.forename: Robert
authors.initials: R
authors.lastname: Goodnow
authors.forename: William
authors.initials: W
authors.lastname: Harris
authors.forename: Phil
authors.initials: P
authors.lastname: Jones
authors.forename: Mikio
authors.initials: M
authors.lastname: Taniguchi
authors.forename: Shinji
authors.initials: S
authors.lastname: Tsujii
authors.forename: Wolfgang
authors.initials: W
authors.lastname: von der Saal
authors.forename: Gerd
authors.initials: G
authors.lastname: Zimmermann
authors.forename: Gisbert
authors.initials: G
authors.lastname: Schneider
mesh_terms: D016208:Databases, Factual; D016014:Linear Models; D015394:Molecular Structure; D016571:Neural Networks, Computer; D017711:Nonlinear Dynamics; D009930:Organic Chemicals / Q000737:chemistry*; D004364:Pharmaceutical Preparations / Q000737:chemistry
chemical_list: D009930:Organic Chemicals; D004364:Pharmaceutical Preparations