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An experimentally validated approach to calculate the blood-brain barrier permeability of small molecules

Research output: Contribution to journalArticlepeer-review

Yukun Wang, Erin Gallagher, Christian Jorgensen, Evan P. Troendle, Dan Hu, Peter C. Searson, Martin B. Ulmschneider

Original languageEnglish
Article number6117
JournalScientific Reports
Issue number1
Early online date16 Apr 2019
Accepted/In press18 Mar 2019
E-pub ahead of print16 Apr 2019
Published1 Dec 2019

King's Authors


Drug development for the treatment of central nervous system (CNS) diseases is extremely challenging, in large part due to the difficulty in crossing the blood-brain barrier (BBB). Here we develop and experimentally validate a new in silico method to predict quantitatively the BBB permeability for small-molecule drugs. We show accurate prediction of solute permeabilities at physiological temperature using high-temperature unbiased atomic detail molecular dynamics simulations of spontaneous drug diffusion across BBB bilayers. These simulations provide atomic detail insights into the transport mechanisms, as well as converged kinetics and thermodynamics. The method is validated computationally against physiological temperature simulations for fast-diffusing compounds, as well as experimentally by direct determination of the compound permeabilities using a transwell assay as an in vitro BBB model. The overall agreement of the predicted values with both direct simulations at physiological temperatures and experimental data is excellent. This new tool has the potential to replace current semi-empirical in silico screening and in vitro permeability measurements in CNS drug discovery.

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