Internet Electronic Journal of Molecular Design - IEJMD, ISSN 1538-6414, CODEN IEJMAT

ABSTRACT - Internet Electron. J. Mol. Des. December 2004, Volume 3, Number 12, 750-758

TOPS-MODE and DRAGON Descriptors in QSAR. 1. Skin Permeation Maykel Pérez González, Aliuska Morales Helguera, and Yanisleidy Morales Rodríguez Internet Electron. J. Mol. Des. 2004, 3, 750-758

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Abstract:
The TOPological Sub-Structural MOlecular DEsign (TOPS-MODE) approach has been applied to the study of the permeability coefficient of various compounds through human skin. A model with good statistical parameters was developed (R² = 0.938, S = 0.24, F = 151.06) with the use of the mentioned approach for the 37 organic compounds used in the training set. In contrast, none of nine different approaches, including the use of constitutional (R² = 0.84, S = 0.38), topological (R² = 0.85, S = 0.37), BCUT (R² = 0.84, S = 0.38), 2D autocorrelations (R² = 0.79, S = 0.44), geometrical (R² = 0.87, S = 0.34), RDF (R² = 0.81, S = 0.41), 3D Morse (R² = 0.90, S = 0.29), GETAWAY (R² = 0.87, S = 0.35) and WHIM (R² = 0.70, S = 0.53) descriptors was able to obtain a correlation coefficient superior to 0.9 in the mentioned property with the same number of descriptors. On the other hand, the TOPS-MODE approach obtains the higher cross validation correlation coefficient of the all models (q² = 0.907). In addition the TOPS MODE allows a simple interpretation of the model in comparison with others methodologies. Briefly, this method codifies the molecular structure by means of the edge adjacency matrix E. The E matrix is a square table of order m. The elements of such a matrix (e_ij) are equal to 1 if the bonds i and j are adjacent or 0 otherwise. To codify information related to heteroatoms, the TOPS-MODE approach use B(w_ij) weighted matrices instead of E. The weights (w_ij) are chemically meaningful numbers such as bond distances, bond dipole, bond polarizabilities, or even mathematical expressions involving atomic weights such as hydrophobicity. We have shown that the TOPS-MODE approach is able to describe the permeability of different compounds through human skin. We have developed a model for predicting the permeability coefficient which is both statistically and chemically sound. This model explains more than 93% of the variance in the experimental permeability coefficients and shows good predictive ability in cross-validation. These features are significantly better than those obtained for other nine different methodologies used to predict this property.

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