MI-QSAR models for prediction of corneal permeability of organic compounds

Abstract

Aim: To derive a theoretical model for the prediction of corneal permeability of miscellaneous organic compounds in drug design. Methods: A training set of 28 structurally diverse compounds was used to build up the membrane-interaction quantitative structure-activity relationship (MI-QSAR) models. Intermolecular and intramolecular solute descriptors were computed using molecular mechanics, molecular dynamics simulations and quantum chemistry. The QSAR models were optimized using multidimensional linear regression fitting and a stepwise method. A test set of 8 compounds was evaluated using the models as part of a validation process. Results: Significant MI-QSAR models (R=0.976, S=0.1301, F=70.957) of corneal permeability of organic compounds were constructed. Corneal permeability was found to depend upon the sum of net atomic charges of hydrogen atoms attached to the heteroatoms (N, O), the sum of the absolute values of the net atomic charges of oxygen and nitrogen atoms, the principal moment of inertia (X), the Connolly accessible area and the conformational flexibility of the solute-membrane complex. Conclusion: The MI-QSAR models indicated that the corneal permeability of organic molecules was not only influenced by the organic solutes themselves, but also related to the properties of the solute-membrane complex, that is, the interactions of the molecule with the phospholipid-rich regions of cellular membranes. ©2006 CPS and SIMM.