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Predicting Blood–Brain Barrier Partitioning of Organic Molecules Using Membrane–Interaction QSAR Analysis

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Abstract

Purpose. Membrane-interaction quantitative structure-activity relationship (QSAR) analysis (MI-QSAR) has been used to develop predictive models of blood-brain barrier partitioning of organic compounds by, in part, simulating the interaction of an organic compound with the phospholipid-rich regions of cellular membranes.

Method. A training set of 56 structurally diverse compounds whose blood-brain barrier partition coefficients were measured was used to construct MI-QSAR models. Molecular dynamics simulations were used to determine the explicit interaction of each test compound (solute) with a model DMPC monolayer membrane model. An additional set of intramolecular solute descriptors were computed and considered in the trial pool of descriptors for building MI-QSAR models. The QSAR models were optimized using multidimensional linear regression fitting and a genetic algorithm. A test set of seven compounds was evaluated using the MI-QSAR models as part of a validation process.

Results. Significant MI-QSAR models (R 2 = 0.845, Q 2 = 0.795) of the blood-brain partitioning process were constructed. Blood-brain barrier partitioning is found to depend upon the polar surface area, the octanol/water partition coefficient, and the conformational flexibility of the compounds as well as the strength of their “binding” to the model biologic membrane. The blood-brain barrier partitioning measures of the test set compounds were predicted with the same accuracy as the compounds of the training set.

Conclusion. The MI-QSAR models indicate that the blood-brain barrier partitioning process can be reliably described for structurally diverse molecules provided interactions of the molecule with the phospholipids-rich regions of cellular membranes are explicitly considered.

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Authors and Affiliations

  1. Laboratory of Molecular Modeling and Design (M/C 781), College of Pharmacy, The University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois, 60612-7231

    Manisha Iyer, Rama Mishra, Yi Han & A. J. Hopfinger

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  1. Manisha Iyer
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  2. Rama Mishra
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  3. Yi Han
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  4. A. J. Hopfinger
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Correspondence to A. J. Hopfinger.

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Iyer, M., Mishra, R., Han, Y. et al. Predicting Blood–Brain Barrier Partitioning of Organic Molecules Using Membrane–Interaction QSAR Analysis. Pharm Res 19, 1611–1621 (2002). https://doi.org/10.1023/A:1020792909928

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