title: High-throughput logPo/w determination from UHPLC measurements: Revisiting the chromatographic hydrophobicity index.
abstract: A fast and accurate lipophilicity determination is fundamental in the drug discovery process, as long as it is a relevant property in the absorption, distribution, metabolism, excretion and toxicity (ADMET) of a potential drug substance. In the present work, different models based on chromatographic retention values for a large set of compounds and some of their molecular descriptors (calculated by ACD/Labs or CODESSA programs) have been examined in order to establish reliable equations for logPo/w determination from fast chromatographic hydrophobicity index (CHI) measurements. This appears to be a very interesting high-throughput methodology for screening purposes, since CHI values can be measured by UHPLC in very short runs (<4min) and molecular descriptors can be easily computed from the structure of any compound. The selected final descriptors were Abraham's hydrogen-bond acidity (A) and excess molar refraction (E) from ACD/Labs, and hydrogen-bond acidity HDCA-1/TMSA and HOMO-LUMO polarizability descriptors from CODESSA software. The proposed equations allow an accurate determination of logPo/w with standard errors in the range of 0.4 units.
authors.affiliation: Departament de Química Analítica-Institut de Biomedicina, Universitat de Barcelona, Martí i Franquès 1-11, 08028 Barcelona, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Subirats
authors.affiliation: Departament de Química Analítica-Institut de Biomedicina, Universitat de Barcelona, Martí i Franquès 1-11, 08028 Barcelona, Spain.
authors.forename: Martí
authors.initials: M
authors.lastname: Rosés
authors.affiliation: Departament de Química Analítica-Institut de Biomedicina, Universitat de Barcelona, Martí i Franquès 1-11, 08028 Barcelona, Spain. Electronic address: e.bosch@ub.edu.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Bosch
mesh_terms: D002853:Chromatography, Liquid; D055808:Drug Discovery / Q000295:instrumentation / Q000379:methods; D057166:High-Throughput Screening Assays; D057927:Hydrophobic and Hydrophilic Interactions; D008956:Models, Chemical; D004364:Pharmaceutical Preparations / Q000737:chemistry*
chemical_list: D004364:Pharmaceutical Preparations
keywords: CHI; Chromatographic hydrophobicity index; Lipophilicity; LogP(o/w); Molecular descriptors; Partition coefficient; Partition ratio