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.
Keywords:
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.