The SAMPL5 challenge for embedded-cluster integral equation theory: solvation free energies, aqueous pK ^sub a^, and cyclohexane-water log D

• Published in: Journal of computer-aided molecular design Vol. 30; no. 11; pp. 1035 - 1044
• Main Authors: Tielker, Nicolas, Tomazic, Daniel, Heil, Jochen, Kloss, Thomas, Ehrhart, Sebastian, Güssregen, Stefan, Schmidt, K Friedemann, Kast, Stefan M
• Format: Journal Article
• Language: English
• Published: Dordrecht Springer Nature B.V 01.11.2016
• Subjects: Acidity; Aqueous chemistry; Constants; Cyclohexane; Free energy; Mathematical models; Molecular chemistry; Parametrization; Quantum physics; Root-mean-square errors; Solvation; Solvents; Water distribution
• ISSN: 0920-654X; 1573-4951
• DOI: 10.1007/s10822-016-9939-7

We predict cyclohexane-water distribution coefficients (log D 7.4) 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 (pK a) 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-1 for water and 0.8-0.9 kcal mol-1 for cyclohexane depending on the parametrization. The second one is treated by employing on one hand an empirical pK a model (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 pK a) for training solvation and acidity models. Applying the final models to the log D 7.4 dataset 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.