Hydrophobic Molecular Similarity from MST Fractional Contributions to the Octanol/water Partition Coefficient |
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Authors: | Jordi?Mu?oz-Muriedas Samantha?Perspicace Nuria?Bech Salvatore?Guccione Modesto?Orozco Email author" target="_blank">F?Javier?LuqueEmail author |
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Institution: | (1) Departament de Fisicoquímica, Facultat de Farmàcia, Universitat de Barcelona, Av. Diagonal 643, 08028 Barcelona, Spain;(2) Dipartimento di Scienze Farmaceutiche, Faculty of Pharmacy, University of Catania, viale Andrea Doria 6, Ed. 2, Città Universitaria, I-95125 Catania, Italy;(3) Departament de Bioquímica i Biología Molecular, Facultat de Química, Universitat de Barcelona, c/., Martí i Franqués 1, 08028 Barcelona, Spain;(4) Unitat de Modelització Molecular i Bioinformàtica, Institut de Recerca Biomèdica., Parc Científic de Barcelona, c/. Josep Samitier 1, 08028 Barcelona, Spain;(5) On leave from Dipartimento di Scienze Farmaceutiche, Faculty of Pharmacy, University of Catania, Catania, Italy |
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Abstract: | 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.
J.M.M. and S.P. have contributed equally to this study. |
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Keywords: | molecular similarity octanol/water partition coefficient continuum solvation methods MST model hydrophobicity molecular alignment |
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