Skin permeability prediction with MD simulation sampling spatial and alchemical reaction coordinates

Area of Science:

• Computational chemistry
• Materials science
• Pharmacology

Background:

• Understanding skin permeation is crucial for developing effective transdermal drug delivery systems and assessing cosmetic safety.
• Current methods for predicting skin penetration can be improved with molecular-level insights.

Purpose of the Study:

• To develop advanced molecular dynamics simulation methods for efficient free energy and diffusion coefficient sampling across the skin barrier.
• To predict skin permeability and the impact of penetration enhancers using these new simulation approaches.

Main Methods:

• Utilized novel two-dimensional reaction coordinates within the accelerated weight histogram method.
• Combined spatial coordinate sampling with alchemical perturbation virtual coordinates.
• Simulated 20 permeants to predict their skin penetration properties.

Main Results:

• Achieved improved correlation between predicted and experimental ex vivo/in vitro skin permeation data.
• Demonstrated the efficacy of the new simulation approach in predicting permeant behavior.
• Reported a mean square difference of 0.9 cm² h⁻² for log Kp (experimental-calculated).

Conclusions:

• The presented molecular dynamics simulation approach offers a powerful tool for predicting skin permeability.
• This method can streamline product development for transdermal and topical applications.
• Enhanced prediction capabilities aid in the safety and toxicity assessment of skincare products.