title: Machine learning models for lipophilicity and their domain of applicability.
abstract: Unfavorable lipophilicity and water solubility cause many drug failures; therefore these properties have to be taken into account early on in lead discovery. Commercial tools for predicting lipophilicity usually have been trained on small and neutral molecules, and are thus often unable to accurately predict in-house data. Using a modern Bayesian machine learning algorithm--a Gaussian process model--this study constructs a log D7 model based on 14,556 drug discovery compounds of Bayer Schering Pharma. Performance is compared with support vector machines, decision trees, ridge regression, and four commercial tools. In a blind test on 7013 new measurements from the last months (including compounds from new projects) 81% were predicted correctly within 1 log unit, compared to only 44% achieved by commercial software. Additional evaluations using public data are presented. We consider error bars for each method (model based error bars, ensemble based, and distance based approaches), and investigate how well they quantify the domain of applicability of each model.
authors.affiliation: Fraunhofer FIRST, Kekuléstrasse 7, 12489 Berlin, Germany. timon.schroeter@first.fraunhofer.de
authors.forename: Timon
authors.initials: T
authors.lastname: Schroeter
authors.forename: Anton
authors.initials: A
authors.lastname: Schwaighofer
authors.forename: Sebastian
authors.initials: S
authors.lastname: Mika
authors.forename: Antonius Ter
authors.initials: AT
authors.lastname: Laak
authors.forename: Detlev
authors.initials: D
authors.lastname: Suelzle
authors.forename: Ursula
authors.initials: U
authors.lastname: Ganzer
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Heinrich
authors.forename: Klaus-Robert
authors.initials: KR
authors.lastname: Müller
mesh_terms: D000465:Algorithms; D001185:Artificial Intelligence; D001499:Bayes Theorem; D003663:Decision Trees; D008055:Lipids / Q000737:chemistry*; D008956:Models, Chemical; D015233:Models, Statistical; D015394:Molecular Structure; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D015203:Reproducibility of Results
chemical_list: D008055:Lipids; D004364:Pharmaceutical Preparations