title: Prediction of pH-dependent aqueous solubility of druglike molecules.
abstract: In the present work, the Henderson-Hasselbalch (HH) equation has been employed for the development of a tool for the prediction of pH-dependent aqueous solubility of drugs and drug candidates. A new prediction method for the intrinsic solubility was developed, based on artificial neural networks that have been trained on a druglike PHYSPROP subset of 4548 compounds. For the prediction of acid/base dissociation coefficients, the commercial tool Marvin has been used, following validation on a data set of 467 molecules from the PHYSPROP database. The best performing network for intrinsic solubility predictions has a cross-validated root mean square error (RMSE) of 0.70 log S-units, while the Marvin pKa plug-in has an RMSE of 0.71 pH-units. A data set of 27 drugs with experimentally determined pH-solubility curves was assembled from the literature for the validation of the combined pH-dependent model, giving a mean RMSE of 0.79 log S-units. Finally, the combined model has been applied on profiling the solubility space at low pH of five large vendor libraries.
authors.affiliation: Center for Biological Sequence Analysis, BioCentrum, Technical University of Denmark, DK-2800 Lyngby, Denmark.
authors.forename: Niclas Tue
authors.initials: NT
authors.lastname: Hansen
authors.forename: Irene
authors.initials: I
authors.lastname: Kouskoumvekaki
authors.forename: Flemming Steen
authors.initials: FS
authors.lastname: Jørgensen
authors.forename: Søren
authors.initials: S
authors.lastname: Brunak
authors.forename: Svava Osk
authors.initials: SO
authors.lastname: Jónsdóttir
mesh_terms: D002626:Chemistry, Pharmaceutical / Q000379:methods*; D003460:Crystallization; D019992:Databases as Topic; D015195:Drug Design; D006863:Hydrogen-Ion Concentration; D008956:Models, Chemical; D015233:Models, Statistical; D008962:Models, Theoretical; D016571:Neural Networks, Computer; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D012984:Software; D012995:Solubility; D012997:Solvents; D013678:Technology, Pharmaceutical / Q000379:methods*; D014867:Water / Q000737:chemistry*
chemical_list: D004364:Pharmaceutical Preparations; D012997:Solvents; D014867:Water