QSPR modelling with the topological substructural molecular design approach: β-cyclodextrin complexation

This study aims at developing a quantitative structure-property relationship (QSPR) model for predicting complexation with β-cyclodextrins (β-CD) based on a large variety of organic compounds. Molecular descriptors were computed following the TOPological Substructural MOlecular DEsign (TOPS-MODE) approach and correlated with β-CD complex stability constants by linear multivariate data analysis. This strategy afforded a final QSPR model that was able to explain around 86% of the variance in the experimental activity, along with showing good internal cross-validation statistics, and also good predictivity on external data. Topological substructural information influencing the complexation with β-CD was extracted from the QSPR model. This revealed that the major driving forces for complexation are hydrophobicity and van der Waals interactions. Therefore, the presence of hydrophobic groups (hydrocarbon chains, aryl groups, etc.) and voluminous species (Cl, Br, I, etc.) in the molecules renders easy their complexity with β-CDs. To our knowledge, this is the first time a correlation between TOPS-MODE descriptors and complexing abilities of β-CDs has been reported. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:4557-4576, 2009