Xiang Tian-Xiang, Anderson Bradley D
Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA.
Adv Drug Deliv Rev. 2006 Nov 30;58(12-13):1357-78. doi: 10.1016/j.addr.2006.09.002. Epub 2006 Sep 22.
Computational methods to predict drug permeability across biomembranes prior to synthesis are increasingly desirable to minimize the investment in drug design and development. Significant progress in molecular dynamics (MD) simulation methodologies applied to lipid bilayer membranes, for example, is making it possible to move beyond characterization of the membranes themselves to explore various thermodynamic and kinetic processes governing membrane binding and transport. Such methods are also likely to be directly applicable to the design and optimization of liposomal delivery systems. MD simulations are particularly valuable in addressing issues that are difficult to explore in laboratory experiments due to the heterogeneity of lipid bilayer membranes at the molecular level. Insights emerging from MD simulations are contributing to an understanding of which regions within bilayers are most and least favored by solutes at equilibrium as the solute structure is varied, local diffusivities of permeants, and the origin of the amplified selectivity to permeant size imposed by lipid bilayer membranes, particularly as changes in composition increase acyl chain ordering.
在药物合成之前预测药物跨生物膜渗透性的计算方法，对于尽量减少药物设计和开发中的投入越来越重要。例如，应用于脂质双分子层膜的分子动力学（MD）模拟方法取得了重大进展，使得人们有可能超越对膜本身的表征，去探索控制膜结合和转运的各种热力学和动力学过程。这些方法也可能直接适用于脂质体递送系统的设计和优化。由于脂质双分子层膜在分子水平上的异质性，MD模拟在解决实验室实验中难以探索的问题方面特别有价值。MD模拟得出的见解有助于理解随着溶质结构的变化，双层膜内哪些区域在平衡时最受溶质青睐、哪些区域最不受青睐，渗透物的局部扩散系数，以及脂质双分子层膜对渗透物大小的放大选择性的来源，特别是随着组成变化导致酰基链有序性增加的情况。
