title: Binding Free Energy Calculations for Lead Optimization: Assessment of Their Accuracy in an Industrial Drug Design Context.
abstract: Correctly ranking compounds according to their computed relative binding affinities will be of great value for decision making in the lead optimization phase of industrial drug discovery. However, the performance of existing computationally demanding binding free energy calculation methods in this context is largely unknown. We analyzed the performance of the molecular mechanics continuum solvent, the linear interaction energy (LIE), and the thermodynamic integration (TI) approach for three sets of compounds from industrial lead optimization projects. The data sets pose challenges typical for this early stage of drug discovery. None of the methods was sufficiently predictive when applied out of the box without considering these challenges. Detailed investigations of failures revealed critical points that are essential for good binding free energy predictions. When data set-specific features were considered accordingly, predictions valuable for lead optimization could be obtained for all approaches but LIE. Our findings lead to clear recommendations for when to use which of the above approaches. Our findings also stress the important role of expert knowledge in this process, not least for estimating the accuracy of prediction results by TI, using indicators such as the size and chemical structure of exchanged groups and the statistical error in the predictions. Such knowledge will be invaluable when it comes to the question which of the TI results can be trusted for decision making.
authors.affiliation: Institute for Pharmaceutical and Medicinal Chemistry, Department of Mathematics and Natural Sciences, Heinrich-Heine-University Düsseldorf , Universitätsstr.1, 40225 Düsseldorf, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Homeyer
authors.affiliation: Global Drug Discovery, Medicinal Chemistry, Bayer Pharma AG , Aprather Weg 18A, 42113 Wuppertal, Germany.
authors.forename: Friederike
authors.initials: F
authors.lastname: Stoll
authors.affiliation: Global Drug Discovery, Medicinal Chemistry, Bayer Pharma AG , Aprather Weg 18A, 42113 Wuppertal, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Hillisch
authors.affiliation: Institute for Pharmaceutical and Medicinal Chemistry, Department of Mathematics and Natural Sciences, Heinrich-Heine-University Düsseldorf , Universitätsstr.1, 40225 Düsseldorf, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Gohlke