title: Development and validation of hydrophobic molecular fields derived from the quantum mechanical IEF/PCM-MST solvation models in 3D-QSAR.
abstract: Since the development of structure-activity relationships about 50 years ago, 3D-QSAR methods belong to the most refined ligand-based in silico techniques for prediction of biological data using physicochemical molecular fields. In this scenario, this study reports the development and validation of quantum mechanical (QM)-based hydrophobic descriptors derived from the parametrized MST continuum solvation model to be used in 3D-QSAR studies within the framework of the Hydrophobic Pharmacophore (HyPhar) method. To this end, five sets of compounds reported in the literature (dopamine D2/D4 antagonists, antifungal 2-aryl-4-chromanones, and inhibitors of GSK-3, cruzain and thermolysin) have been revisited. The results derived from the QM/MST-based hydrophobic descriptors have been compared with previous CoMFA and CoMSIA studies, and examined in light of the available X-ray crystallographic structures of the targets. The analysis reveals that the combination of electrostatic and nonelectrostatic components of the octanol/water partition coefficient yields pharmacophoric models fully comparable with the predictive potential of standard 3D-QSAR techniques. Moreover, the graphical representation of the hydrophobic maps provides a direct linkage with the pattern of interactions found in crystallographic structures. Overall, the introduction of the QM/MST-based descriptors, which could be easily adapted to other continuum solvation formalisms, paves the way to novel computational strategies for disclosing structure-activity relationships in drug design. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Dipartimento Di Scienze Degli Alimenti, University of Parma, Parco Area Delle Scienze 59/a, Parma, 43121, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Ginex
authors.affiliation: GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, SG1 2NY, United Kingdom.
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, Barcelona, 08034, 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, Barcelona, 08034, Spain.
authors.forename: Enric
authors.initials: E
authors.lastname: Gibert
authors.affiliation: Dipartimento Di Scienze Degli Alimenti, University of Parma, Parco Area Delle Scienze 59/a, Parma, 43121, Italy.
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, Santa Coloma De Gramenet, 08921, Spain.
authors.forename: F J
authors.initials: FJ
authors.lastname: Luque
keywords: 3D-QSAR; continuum solvation model; hydrophobic molecular field; quantum mechanics