Developing Enhanced Blood–Brain Barrier Permeability Models: Integrating External Bio-Assay Data in QSAR Modeling
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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 R2 = 0.638 for five-fold cross-validation and R2 = 0.504 for external validation. The consensus model developed by pooling chemical and transporter descriptors showed better predictivity (R2 = 0.646 for five-fold cross-validation and R2 = 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.
KEY WORDSbiological descriptors blood–brain barrier hybrid model permeability
Absorption, distribution, metabolism, and excretion
PubChem bio-assay identifier
Aldehyde dehydrogenase 1 family, member A1
Apical sodium-dependent bile acid transporter
Bile salt export pump
Cyclic adenosine monophosphate
PubChem compound identifier
Central nervous system
Estrogen receptor alpha
Human intestinal transporters
High throughput screening
Logarithm of brain-plasma concentration ratio at steady-state
Mean absolute error
Monocarboxylic acid transporters
Multidrug resistance protein 1
Molecular operating environment software
Multidrug resistance-associated protein 1
Multidrug resistance-associated protein 3
Multidrug resistance-associated protein 4
Multidrug resistance-associated protein 5
Organic anion transporting polypeptides
Principle component analysis
Quantitative structure-activity relationship
Support vector machine
ACKNOWLEDGMENTS AND DISCLOSURES
Research reported in this publication was supported, in part, by the National Institute of Environmental Health Sciences of the National Institutes of Health under Award Number R15ES023148 and the Colgate-Palmolive Grant for Alternative Research. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
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