Explaining Blood-Brain Barrier Permeability of Small Molecules by Integrated Analysis of Different Transport Mechanisms

摘要

The blood-brain barrier (BBB) represents a majorobstacleto delivering drugs to the central nervous system (CNS), resultingin the lack of effective treatment for many CNS diseases includingbrain cancer. To accelerate CNS drug development, computational predictionmodels could save the time and effort needed for experimental evaluation.Here, we studied BBB permeability focusing on active transport (influxand efflux) as well as passive diffusion using previously publishedand self-curated data sets. We created prediction models based onphysicochemical properties, molecular substructures, or their combinationto understand which mechanisms contribute to BBB permeability. Ourresults show that features that predicted passive diffusion over membranesoverlap with features that explain endothelial permeation of approvedCNS-active drugs. We also identified physical properties and molecularsubstructures that positively or negatively predicted BBB transport.These findings provide guidance toward identifying BBB-permeable compoundsby optimally matching physicochemical and molecular properties toBBB transport mechanisms.