Prediction of the Corneal Permeability of Drug-Like Compounds



To develop a computational model for optimisation of low corneal permeability, which is a key feature in ocular drug development.


We have used multivariate analysis to build corneal permeability models based on a structurally diverse set of 58 drug-like compounds.


According to the models, the most important parameters for permeability are logD at physiologically relevant pH and the number of hydrogen bonds that can be formed. Combining these descriptors resulted in models with Q 2 and R 2 values ranging from 0.77 to 0.79. The predictive capability of the models was verified by estimating the corneal permeability of an external data set of 11 compounds and by using predicted permeability values to calculate the aqueous humour concentrations in the steady-state of seven compounds. The predicted values correlated well with experimental values.


The developed models are useful in early drug development to predict the corneal permeability and steady-state drug concentration in aqueous humor without experimental data.

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Fig. 1
Fig. 2
Fig. 3


Css :

steady-state concentration


number of hydrogen bond acceptors


number of hydrogen bond donors

HBtot :

total number of putative hydrogen bonds, i.e. HBD + HBA


the logarithm of the octanol-water partition coefficient of the neutral form

logperm :

the logarithm of the corneal permeability

logD7.0, logD7.4 and logD8.0 :

the logarithm of the octanol-water partition coefficient at pH 7.0, 7.4 and 8.0, respectively


molecular volume


molecular weight


principal component analysis


partial least squares


polar surface area


quantitative structure-property relationship


root mean squared error


root mean squared error of prediction


variable importance in the projection


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This work was supported by the Academy of Finland. Heikki Käsnänen is thanked for valuable comments on the manuscript.

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Correspondence to Arto Urtti.

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Kidron, H., Vellonen, KS., del Amo, E.M. et al. Prediction of the Corneal Permeability of Drug-Like Compounds. Pharm Res 27, 1398–1407 (2010).

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  • computational model
  • multivariate analysis
  • ocular absorption
  • ophthalmic drugs
  • QSPR