title: Application of the quantum mechanical IEF/PCM-MST hydrophobic descriptors to selectivity in ligand binding.
abstract: We have recently reported the development and validation of quantum mechanical (QM)-based hydrophobic descriptors derived from the parametrized IEF/PCM-MST continuum solvation model for 3D-QSAR studies within the framework of the Hydrophobic Pharmacophore (HyPhar) method. In this study we explore the applicability of these descriptors to the analysis of selectivity fields. To this end, we have examined a series of 88 compounds with inhibitory activities against thrombin, trypsin and factor Xa, and the HyPhar results have been compared with 3D-QSAR models reported in the literature. The quantitative models obtained by combining the electrostatic and non-electrostatic components of the octanol/water partition coefficient yield results that compare well with the predictive potential of standard CoMFA and CoMSIA techniques. The results also highlight the potential of HyPhar descriptors to discriminate the selectivity of the compounds against thrombin, trypsin, and factor Xa. Moreover, the graphical representation of the hydrophobic maps provides a direct linkage with the pattern of interactions found in crystallographic structures. Overall, the results support the usefulness of the QM/MST-based hydrophobic descriptors as a complementary approach for disclosing structure-activity relationships in drug design and for gaining insight into the molecular determinants of ligand selectivity. Graphical Abstract Quantum Mechanical continuum solvation calculations performed with the IEF/PCM-MST method are used to derived atomic hydrophobic descriptors, which are then used to discriminate the selectivity of ligands against thrombin, trypsin and factor Xa. The descriptors provide complementary view to standard 3D-QSAR analysis, leading to a more comprehensive understanding of ligand recognition.
authors.affiliation: Department of Food Science, University of Parma, Parco Area delle Scienze 59/A, 43121, Parma, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Ginex
authors.affiliation: GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, SG1 2NY, UK.
authors.forename: Jordi
authors.initials: J
authors.lastname: Muñoz-Muriedas
authors.affiliation: Pharmacelera, Jordi Girona 1-3, Campus Nord Universitat Politècnica de Catalunya, Edifici K2M, 08034, Barcelona, Spain.
authors.forename: Enric
authors.initials: E
authors.lastname: Herrero
authors.affiliation: Pharmacelera, Jordi Girona 1-3, Campus Nord Universitat Politècnica de Catalunya, Edifici K2M, 08034, Barcelona, Spain.
authors.forename: Enric
authors.initials: E
authors.lastname: Gibert
authors.affiliation: Department of Food Science, University of Parma, Parco Area delle Scienze 59/A, 43121, Parma, Italy. pietro.cozzini@unipr.it.
authors.forename: Pietro
authors.initials: P
authors.lastname: Cozzini
authors.affiliation: Department of Chemical Physics and Institut de Biomedicina (IBUB), Faculty of Pharmacy, University of Barcelona, Av. Prat de la Riba 171, 08921, Santa Coloma de Gramenet, Spain. fjluque@ub.edu.
authors.forename: F Javier
authors.initials: FJ
authors.lastname: Luque
keywords: 3D-QSAR; Continuum solvation model; Hydrophobic molecular field; Target selectivity