Classical QSAR and comparative molecular field analyses of the host-guest interaction of organic molecules with...

The application of classical QSAR and molecular modeling analysis using Comparative Molecular Field Analysis (CoMFA) to the complexation of some natural and modified cyclodextrins (CDs) with guest molecules was examined. For 1:1 complexation systems between natural beta-CD, modified alpha-, beta-, and gamma-CD that bear one p-(dimethylamino)benzoyl (DMAB) moiety (DMAB-alpha-, beta-, and gamma-CDs) and guest molecules of widely varying chemical structures and properties, the binding constants of the complexes were successfully fitted using multiple linear regression (MLR) with hydrophobic descriptor log P (the partition coefficient between 1-octanol and water phases) and molecular connectivity indices. A non-linear dependency of binding constants on the zero-th and/or first order molecular connectivity index as a measure of size becomes apparent. The modeling performance of the CoMFA models with steric/electrostatic fields to DMAB-alpha- and beta-CD systems was comparable to those of MLR models. However, statistically significant CoMFA models for gamma-CD systems which have higher conformational flexibility of the ring could not be obtained. The CoMFA models obtained for DMAB-alpha- and beta-CD systems showed that the predominant effects were steric for the DMAB-alpha-CD system and electrostatic for the DMAB-beta-CD system, respectively.