Abstract

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.

Details

Title
An experimentally validated approach to calculate the blood-brain barrier permeability of small molecules
Author
Wang, Yukun 1 ; Gallagher, Erin 1 ; Jorgensen, Christian 1   VIAFID ORCID Logo  ; Troendle, Evan P 2   VIAFID ORCID Logo  ; Hu, Dan 3 ; Searson, Peter C 4   VIAFID ORCID Logo  ; Ulmschneider, Martin B 2 

 Johns Hopkins University, Institute for NanoBioTechnology, Baltimore, USA (GRID:grid.21107.35) (ISNI:0000 0001 2171 9311) 
 King’s College London, Department of Chemistry, London, UK (GRID:grid.13097.3c) (ISNI:0000 0001 2322 6764) 
 Shanghai Jiao-Tong University, Institute of Natural Sciences and Department of Mathematics, Shanghai, China (GRID:grid.16821.3c) (ISNI:0000 0004 0368 8293) 
 Johns Hopkins University, Institute for NanoBioTechnology, Baltimore, USA (GRID:grid.21107.35) (ISNI:0000 0001 2171 9311); Johns Hopkins University, Department of Materials Science and Engineering, Baltimore, USA (GRID:grid.21107.35) (ISNI:0000 0001 2171 9311) 
Publication year
2019
Publication date
2019
Publisher
Nature Publishing Group
e-ISSN
20452322
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2210431157
Copyright
© The Author(s) 2019. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.