Journal of Computer-Aided Molecular Design

, Volume 19, Issue 6, pp 401–419

Hydrophobic Molecular Similarity from MST Fractional Contributions to the Octanol/water Partition Coefficient

  • Jordi Muñoz-Muriedas
  • Samantha Perspicace
  • Nuria Bech
  • Salvatore Guccione
  • Modesto Orozco
  • F. Javier Luque
Article

DOI: 10.1007/s10822-005-7928-3

Cite this article as:
Muñoz-Muriedas, J., Perspicace, S., Bech, N. et al. J Comput Aided Mol Des (2005) 19: 401. doi:10.1007/s10822-005-7928-3

Summary

The use of a recently proposed hydrophobic similarity index for the alignment of molecules and the prediction of their differences in biological activity is described. The hydrophobic similarity index exploits atomic contributions to the octanol/water transfer free energy, which are evaluated by means of the fractional partitioning scheme developed within the framework of the Miertus-Scrocco-Tomasi continuum model. Those contributions are used to define global and local measures of hydrophobic similarity. The suitability of this computational strategy is examined for two series of compounds (ACAT inhibitors and 5-HT3 receptor agonists), which are aligned to maximize the global hydrophobic similarity using a Monte Carlo-simulated protocol. Indeed, the concept of local hydrophobic similarity is used to explore structure–activity relationships in a series of COX-2 inhibitors. Inspection of the 3D distribution of hydrophobic/hydrophilic contributions in the aligned molecules is valuable to identify regions of very similar hydrophobicity, which can define pharmacophoric recognition patterns. Moreover, low similar regions permit to identify structural elements that modulate the differences in activity between molecules. Finally, the quantitative relationships found between the pharmacological activity and the hydrophobic similarity index points out that not only the global hydrophobicity, but its 3D distribution, is important to gain insight into the activity of molecules.

Keywords

molecular similarityoctanol/water partition coefficientcontinuum solvation methodsMST modelhydrophobicitymolecular alignment

Copyright information

© Springer 2005

Authors and Affiliations

  • Jordi Muñoz-Muriedas
    • 1
  • Samantha Perspicace
    • 2
    • 5
  • Nuria Bech
    • 1
  • Salvatore Guccione
    • 2
  • Modesto Orozco
    • 3
    • 4
  • F. Javier Luque
    • 1
  1. 1.Departament de Fisicoquímica, Facultat de FarmàciaUniversitat de BarcelonaBarcelonaSpain
  2. 2.Dipartimento di Scienze Farmaceutiche, Faculty of PharmacyUniversity of CataniaCataniaItaly
  3. 3.Departament de Bioquímica i Biología Molecular, Facultat de QuímicaUniversitat de BarcelonaBarcelonaSpain
  4. 4.Unitat de Modelització Molecular i Bioinformàtica, Institut de Recerca Biomèdica.Parc Científic de BarcelonaBarcelonaSpain
  5. 5.On leave from Dipartimento di Scienze Farmaceutiche, Faculty of PharmacyUniversity of CataniaCataniaItaly