Application of the quantum mechanical IEF/PCM-MST hydrophobic descriptors to selectivity in ligand binding

  • Tiziana Ginex
  • Jordi Muñoz-Muriedas
  • Enric Herrero
  • Enric Gibert
  • Pietro CozziniEmail author
  • F. Javier LuqueEmail author
Original Paper
Part of the following topical collections:
  1. MIB 2015 (Modeling Interaction in Biomolecules VII)


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.


Target selectivity Hydrophobic molecular field Continuum solvation model 3D-QSAR 



We thank the financial support from Ministerio de Economía y Competitividad (SAF2014-57094-R) and the Generalitat de Catalunya (2014-SGR-1189). We are grateful to the Consorci de Serveis Universitaris de Catalunya (CSUC) for computational resources. FJL acknowledges the support from ICREA Academia.

Supplementary material

894_2016_2991_MOESM1_ESM.docx (4 mb)
ESM 1 (DOCX 4103 kb)


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Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Tiziana Ginex
    • 1
  • Jordi Muñoz-Muriedas
    • 2
  • Enric Herrero
    • 3
  • Enric Gibert
    • 3
  • Pietro Cozzini
    • 1
    Email author
  • F. Javier Luque
    • 4
    Email author
  1. 1.Department of Food ScienceUniversity of ParmaParmaItaly
  2. 2.GlaxoSmithKline, Medicines Research CentreStevenageUK
  3. 3.PharmaceleraBarcelonaSpain
  4. 4.Department of Chemical Physics and Institut de Biomedicina (IBUB), Faculty of PharmacyUniversity of BarcelonaSanta Coloma de GramenetSpain

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