Developing Enhanced Blood-Brain Barrier Permeability Models: Integrating External Bio-Assay Data in QSAR Modeling.

Abstract

Experimental Blood-Brain Barrier (BBB) permeability models for drug molecules are expensive and time-consuming. As alternative methods, several traditional Quantitative Structure-Activity Relationship (QSAR) models have been developed previously. In this study, we aimed to improve the predictivity of traditional QSAR BBB permeability models by employing relevant public bio-assay data in the modeling process. We compiled a BBB permeability database consisting of 439 unique compounds from various resources. The database was split into a modeling set of 341 compounds and a validation set of 98 compounds. Consensus QSAR modeling workflow was employed on the modeling set to develop various QSAR models. A five-fold cross-validation approach was used to validate the developed models, and the resulting models were used to predict the external validation set compounds. Furthermore, we used previously published membrane transporter models to generate relevant transporter profiles for target compounds. The transporter profiles were used as additional biological descriptors to develop hybrid QSAR BBB models. The consensus QSAR models have R(2) = 0.638 for five-fold cross-validation and R(2) = 0.504 for external validation. The consensus model developed by pooling chemical and transporter descriptors showed better predictivity (R(2) = 0.646 for five-fold cross-validation and R(2) = 0.526 for external validation). Moreover, several external bio-assays that correlate with BBB permeability were identified using our automatic profiling tool. The BBB permeability models developed in this study can be useful for early evaluation of new compounds (e.g., new drug candidates). The combination of chemical and biological descriptors shows a promising direction to improve the current traditional QSAR models.