title: The SAMPL5 challenge for embedded-cluster integral equation theory: solvation free energies, aqueous pKa, and cyclohexane-water log D.
abstract: We predict cyclohexane-water distribution coefficients (log D7.4) for drug-like molecules taken from the SAMPL5 blind prediction challenge by the "embedded cluster reference interaction site model" (EC-RISM) integral equation theory. This task involves the coupled problem of predicting both partition coefficients (log P) of neutral species between the solvents and aqueous acidity constants (pKa) in order to account for a change of protonation states. The first issue is addressed by calibrating an EC-RISM-based model for solvation free energies derived from the "Minnesota Solvation Database" (MNSOL) for both water and cyclohexane utilizing a correction based on the partial molar volume, yielding a root mean square error (RMSE) of 2.4 kcal mol-1for water and 0.8-0.9 kcal mol-1for cyclohexane depending on the parametrization. The second one is treated by employing on one hand an empirical pKamodel (MoKa) and, on the other hand, an EC-RISM-derived regression of published acidity constants (RMSE of 1.5 for a single model covering acids and bases). In total, at most 8 adjustable parameters are necessary (2-3 for each solvent and two for the pKa) for training solvation and acidity models. Applying the final models to the log D7.4dataset corresponds to evaluating an independent test set comprising other, composite observables, yielding, for different cyclohexane parametrizations, 2.0-2.1 for the RMSE with the first and 2.2-2.8 with the combined first and second SAMPL5 data set batches. Notably, a pure log P model (assuming neutral species only) performs statistically similarly for these particular compounds. The nature of the approximations and possible perspectives for future developments are discussed.
authors.affiliation: Physikalische Chemie III, Technische Universität Dortmund, Otto-Hahn-Str. 4a, 44227, Dortmund, Germany.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Tielker
authors.affiliation: Physikalische Chemie III, Technische Universität Dortmund, Otto-Hahn-Str. 4a, 44227, Dortmund, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Tomazic
authors.affiliation: Physikalische Chemie III, Technische Universität Dortmund, Otto-Hahn-Str. 4a, 44227, Dortmund, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Heil
authors.affiliation: IPhT, L'Orme des Merisiers, CEA-Saclay, 91191, Gif-sur-Yvette, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Kloss
authors.affiliation: CERN, 1211, Geneva, Switzerland.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Ehrhart
authors.affiliation: Sanofi-Aventis Deutschland GmbH, Industriepark Höchst, 65926, Frankfurt am Main, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Güssregen
authors.affiliation: Sanofi-Aventis Deutschland GmbH, Industriepark Höchst, 65926, Frankfurt am Main, Germany.
authors.forename: K Friedemann
authors.initials: KF
authors.lastname: Schmidt
authors.affiliation: Physikalische Chemie III, Technische Universität Dortmund, Otto-Hahn-Str. 4a, 44227, Dortmund, Germany. stefan.kast@tu-dortmund.de.
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Kast
mesh_terms: D003198:Computer Simulation; D003510:Cyclohexanes / Q000737:chemistry*; D008956:Models, Chemical; D015394:Molecular Structure; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D011789:Quantum Theory; D012995:Solubility; D012997:Solvents / Q000737:chemistry; D013816:Thermodynamics; D014867:Water / Q000737:chemistry*
chemical_list: D003510:Cyclohexanes; D004364:Pharmaceutical Preparations; D012997:Solvents; D014867:Water; C506365:Cyclohexane
keywords: Distribution coefficients; EC-RISM; Integral equation theory; Quantum chemistry; Solvation model