Curtin Medical School, Curtin Health Innovation Research Institute and Curtin Institute for Computation, Curtin University, GPO Box U1987, Perth, WA 5845, Australia.
Basil Hetzel Institute for Translational Health Research, 37a Woodville Road, Woodville South, SA 5011, Australia.
Int J Mol Sci. 2022 Dec 15;23(24):16001. 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 .
皮肤的外层构成了一道几乎不可渗透的屏障，使外源性物质难以进入。只有少数具有低分子量的亲脂性药物可以被动扩散通过这一层，这突出表明需要开发方法来促进更多药物经皮给药。前药方法涉及修饰药物分子的结构以增强其穿过皮肤的通透性，但通常很难预测化学结构的变化如何确切地影响渗透。本研究使用分子动力学模拟来预测通透性值，并充分描述 Me-5ALA 前药及其母体化合物 5ALA 在人 脂质双层分子模型中渗透的分子机制。Me-5ALA 疏水性增加对其渗透的影响揭示了其氢键能力的降低，这使其能够更有利地与双层的疏水区相互作用，并以更快的速度扩散，阻力更小，因此与亲水性更强的母体化合物相比，它是一种更好的渗透剂。这种分子模拟方法为合理设计能够有效穿透 的药物分子提供了一条有前途的途径。
