Simulating the Skin Permeation Process of Ionizable Molecules
Magnus Lundborg1,2, Christian Wennberg1,3, Erik Lindahl4,5
1SciLifeLab, ERCO Pharma AB, 171 65 Solna, Sweden.
Journal of Chemical Information and Modeling
|June 25, 2024
Summary
Ionizable drug molecules permeate the skin barrier. While dynamic protonation simulations offer insights, calculations of skin permeability coefficients can rely solely on the neutral form of these molecules.
Area of Science:
- Pharmacokinetics
- Computational Chemistry
- Materials Science
Background:
- Ionizable molecules, like drugs, are crucial in pharmaceuticals.
- The skin barrier presents a significant challenge for drug delivery.
- Current models often assume passive diffusion of neutral drug species.
Purpose of the Study:
- To investigate the dynamic protonation behavior of ionizable molecules during skin permeation.
- To determine if dynamic protonation simulations are necessary for calculating skin permeability coefficients.
- To compare the permeation of weak acids versus weak bases through lipid bilayers.
Main Methods:
- Molecular dynamics (MD) simulations were employed.
- Simulations were conducted separately for charged and neutral states of molecules.
- Three weak acids and three weak bases were studied across a lipid barrier model.
Main Results:
- Weak acids showed higher ionization than weak bases in the lipid headgroup region near their pKa.
- Dynamic protonation simulations provided informative data on molecular behavior.
- However, these dynamic simulations were not essential for permeability coefficient calculations in the studied cases.
Conclusions:
- Skin permeability calculations can effectively utilize only the neutral form of ionizable molecules.
- The assumption of neutral form permeation is sufficient for calculating permeability coefficients.
- Understanding dynamic protonation is valuable but not always required for quantitative predictions.
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