Characterisation of the Molecular Mechanism of Permeation of the Prodrug Me-5ALA across the Human Stratum Corneum Using Molecular Dynamics Simulations

• Published in: International journal of molecular sciences 2022-12, Vol.23 (24), p.16001
• Main Authors: Kadyrov, Janonna, Ruiz-Perez, Lanie, Benson, Heather A E, Mancera, Ricardo L
• Format: Article
• Language: English
• Subjects: Acne; Administration, Cutaneous; Cytotoxicity; Drug delivery; Drug development; Drug dosages; drug lipidation; drug permeation; Drugs; Dynamic structural analysis; Energy; Humans; Hydrogen bonding; Hydrophobicity; lipid bilayer; Lipid bilayers; Lipids; Lipophilic; Molecular dynamics; Molecular Dynamics Simulation; Molecular structure; Permeability; prodrug; Prodrugs; Prodrugs - chemistry; Product development; Simulation; Skin - metabolism; Skin Absorption; Stratum corneum; transdermal drug delivery; Transdermal medication
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms232416001

The barrier imposed by the outer layer of the skin, the , creates an almost impermeable environment for exogenous substances. Few lipophilic drugs with low molecular mass can passively diffuse through this layer, highlighting the need to develop methods to enable the delivery of more drugs via the transdermal route. The prodrug approach involves modifying the structure of a drug molecule to enhance its permeability across the skin, but it is often difficult to predict how exactly changes in chemical structure affect permeation. This study uses molecular dynamics simulations to predict permeability values and adequately characterise the molecular mechanism of permeation of the prodrugs Me-5ALA and its parent compound 5ALA across a molecular model of the lipid bilayers of the human . The influence of increased hydrophobicity in Me-5ALA on its permeation revealed a reduction in hydrogen bonding capability that enables it to interact more favourably with the hydrophobic region of the bilayer and diffuse at a faster rate with less resistance, thus making it a better permeant compared to its more hydrophilic parent compound. This molecular simulation approach offers a promising route for the rational design of drug molecules that can permeate effectively across the .