Journal
JOURNAL OF CHEMICAL INFORMATION AND MODELING
Volume 59, Issue 1, Pages 236-244Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jcim.8b00744
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- Novartis Institutes for BioMedical Research
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A simple descriptor calculated from molecular dynamics simulations of the membrane partitioning event is found to correlate well with experimental measurements of passive membrane permeation from the high-throughput MDCK-LE assay using a data set of 49 drug-like molecules. This descriptor approximates the energy cost of translocation across the hydrophobic membrane core (flip-flop), which for many molecules limits permeability. Performance is found to be superior in comparison to calculated properties such as clogP, clogD, or polar surface area. Furthermore, the atomistic simulations provide a structural understanding of the partitioned drug-membrane complex, facilitating medicinal chemistry optimization of membrane permeability.
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