Drug Bioinformatics Group, Helmholtz Centre for Infection Research (HZI), Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Saarbrücken66123, Germany.
Department of Biological Barriers and Drug Delivery, Helmholtz Centre for Infection Research (HZI), Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Saarbrücken66123, Germany.
J Chem Inf Model. 2022 Oct 24;62(20):5023-5033. doi: 10.1021/acs.jcim.2c00767. Epub 2022 Oct 10.
Passive diffusion across biomembranes is an important mechanism of permeation for multiple drugs, including antibiotics. However, this process is frequently neglected while studying drug uptake and, in our view, warrants further investigation. Here, we apply molecular dynamics simulations to investigate the impact of changes in molecular hydrophobicity on the permeability of a series of inhibitors of the quorum sensing of , previously discovered by us, across a membrane model. Overall, we show that permeation across this membrane model does not correlate with the molecule's hydrophobicity. We demonstrate that using a simple model for permeation, based on the difference between the maximum and minimum of the free energy profile, outperforms the inhomogeneous solubility-diffusion model, yielding a permeability ranking that better agrees with the experimental results, especially for hydrophobic permeants. The calculated differences in permeability could not explain differences in activity. Nevertheless, substantial differences in molecular orientation along the permeation pathway correlate with the activity, emphasizing the importance of analyzing, at an atomistic level, the permeation pathway of these solutes.
生物膜的被动扩散是多种药物（包括抗生素）渗透的重要机制。然而，在研究药物摄取时，这一过程经常被忽视，我们认为有必要进一步研究。在这里，我们应用分子动力学模拟来研究分子疏水性变化对我们先前发现的群体感应抑制剂系列在膜模型中渗透性的影响。总的来说，我们表明，跨膜模型的渗透与分子疏水性无关。我们证明，使用基于自由能分布最大值和最小值之间差异的简单渗透模型优于非均相溶解-扩散模型，得出的渗透性排序与实验结果更吻合，特别是对于疏水性渗透物。计算出的渗透性差异并不能解释活性的差异。然而，渗透途径中分子取向的显著差异与活性相关，这强调了在原子水平上分析这些溶质渗透途径的重要性。
