title: Integrated decision support for assessing chemical liabilities.
abstract: Chemical liabilities, such as adverse effects and toxicity, have a major impact on today's drug discovery process. In silico prediction of chemical liabilities is an important approach which can reduce costs and animal testing by complementing or replacing in vitro and in vivo liability models. There is a lack of integrated, extensible decision support systems for chemical liability assessment which run quickly and have easily interpretable results. Here we present a method which integrates similarity searches, structural alerts, and QSAR models which all are available from the Bioclipse workbench. Emphasis has been placed on interpretation of results, and substructures which are important for predictions are highlighted in the original chemical structures. This allows for interactively changing chemical structures with instant visual feedback and can be used for hypothesis testing of single chemical structures as well as compound collections. The system has a clear separation between methods and data, and the extensible architecture enables straightforward extension via addition of more plugins (such as new data sets and computational models). We demonstrate our method on three important safety end points: mutagenicity, carcinogenicity, and aryl hydrocarbon receptor (AhR) activation. Bioclipse and the decision support implementation are free, open source, and available from http://www.bioclipse.net/decision-support .
authors.affiliation: Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden. ola.spjuth@farmbio.uu.se
authors.forename: Ola
authors.initials: O
authors.lastname: Spjuth
authors.forename: Martin
authors.initials: M
authors.lastname: Eklund
authors.forename: Ernst
authors.initials: E
authors.lastname: Ahlberg Helgee
authors.forename: Scott
authors.initials: S
authors.lastname: Boyer
authors.forename: Lars
authors.initials: L
authors.lastname: Carlsson
mesh_terms: D000465:Algorithms; D002273:Carcinogens / Q000032:analysis* / Q000737:chemistry; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D003198:Computer Simulation; D057225:Data Mining; D016208:Databases, Factual; D015195:Drug Design; D055808:Drug Discovery / Q000379:methods*; D064420:Drug-Related Side Effects and Adverse Reactions / Q000517:prevention & control*; D006801:Humans; D008956:Models, Chemical; D015394:Molecular Structure; D009153:Mutagens / Q000032:analysis* / Q000737:chemistry; D004364:Pharmaceutical Preparations / Q000032:analysis* / Q000737:chemistry; D056510:Position-Specific Scoring Matrices; D021281:Quantitative Structure-Activity Relationship; D018336:Receptors, Aryl Hydrocarbon / Q000032:analysis* / Q000737:chemistry; D012984:Software
chemical_list: D002273:Carcinogens; D009153:Mutagens; D004364:Pharmaceutical Preparations; D018336:Receptors, Aryl Hydrocarbon