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Lecture: An experimentally validated method to predict the blood-brain barrier permeability of small molecules using unbiased molecular dynamics simulations

Speaker: Martin B. Ulmschneider, King’s College London, Department of Chemistry, UK (Host: Birgit Schiøtt)

08.01.2020 | Marianne Sommer

Dato tor 09 jan
Tid 14:00 15:00
Sted Aud III (1514-115), Institut for Kemi, Langelandsgade 140, 8000 Aarhus C


Drug development for the treatment of central nervous system diseases (CNS) is extremely challenging, in large part due to the difficulty in crossing the blood-brain barrier (BBB). At present, there is no method that can reliably predict the BBB permeability of small molecule pharmacophores. This is hindering progress in the development of urgently needed pharmaceuticals to treat CNS disorders such as dementia. Here we present and experimentally validate a new method that predicts quantitatively the BBB permeability for small molecule drugs with high accuracy.

Unlike previous approaches this method is based on equilibrium molecular dynamics simulations that capture the spontaneous transport process across BBB membranes of small molecules multiple times in their entirety and without bias. We show that for slowly diffusing compounds physiological temperature BBB permeabilities can be accurately predicted using high-temperature simulations. These simulations provide atomic detail insights into the transport mechanisms, as well as converged kinetics and thermodynamics.

We validate this method 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.

A key advantage of unbiased equilibrium simulations is that they directly sample the true thermodynamic equilibrium and provide unprecedented atomic detail kinetic and mechanistic insights that correspond to an in silico ‘experiment’ (Ulmschneider et al. PNAS 2013, 110, 6364-6369; Ulmschneider et al. Nature Comm. 2014, 5 (4863), 1-10). This approach, although computationally more costly, is free of any bias, as the simulations reveal the actual translocation pathways and mechanisms, which is not possible with any other method at present.

Institut for Kemi, Medarbejdere, Offentligheden / Pressen