Physics-Based Method for Modeling Passive Membrane Permeability and Translocation Pathways of Bioactive Molecules
Physics-Based Method for Modeling Passive Membrane Permeability and Translocation Pathways of Bioactive Molecules
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DOI：
10.1021/acs.jcim.9b00224
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发表时间：
2019-07-01
影响因子：
5.6
通讯作者：
Pogozheva, Irina D.
中科院分区：
文献类型：
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作者：
Lomize, Andrei L.;Pogozheva, Irina D.
渗透性评估是药物开发过程中选择具有良好ADME性质的候选药物的关键步骤。我们已经开发了一种新的基于物理的方法，用于快速计算建模的被动渗透的不同类别的分子穿过脂质膜。该方法是基于非均相溶解扩散理论和操作的溶质和各向异性溶剂模型的跨双层的介电和氢键容量参数的跨双层配置文件的脂质双层的全原子3D结构。溶质的最佳转运途径是通过将分子的代表性构象的集合移动通过二油酰-磷脂酰胆碱（DOPC）双层并优化它们在跨膜轨迹的每个点中的旋转取向来确定的。该方法计算（1）溶质分子的膜结合态;（2）溶质沿着渗透路径的自由能分布;和（3）通过跨双层能量分布积分并假设沿着膜法线的恒定尺寸依赖性扩散率获得的渗透系数。预测的准确性进行了评估，对实验的渗透系数测量纯脂膜（对于78种化合物，R-2为0.88，rmse为1.15 log单位），PAMPA-DS（280种化合物的R-2为0.75，rmse为1.59 log units），BBB（对于182种化合物，R-2为0.69，rmse为0.87 log单位）和Caco-2/MDCK测定（对于165种化合物，R-2为0.52，rmse为0.89 log单位）。
Assessment of permeability is a critical step in the drug development process for selection of drug candidates with favorable ADME properties. We have developed a novel physics-based method for fast computational modeling of passive permeation of diverse classes of molecules across lipid membranes. The method is based on heterogeneous solubility-diffusion theory and operates with all-atom 3D structures of solutes and the anisotropic solvent model of the lipid bilayer characterized by transbilayer profiles of dielectric and hydrogen bonding capacity parameters. The optimal translocation pathway of a solute is determined by moving an ensemble of representative conformations of the molecule through the dioleoyl-phosphatidylcholine (DOPC) bilayer and optimizing their rotational orientations in every point of the transmembrane trajectory. The method calculates (1) the membrane-bound state of the solute molecule; (2) free energy profile of the solute along the permeation pathway; and (3) the permeability coefficient obtained by integration over the transbilayer energy profile and assuming a constant size-dependent diffusivity along the membrane normal. The accuracy of the predictions was evaluated against experimental permeability coefficients measured in pure lipid membranes (for 78 compounds, R-2 was 0.88 and rmse was 1.15 log units), PAMPA-DS (for 280 compounds, R-2 was 0.75 and rmse was 1.59 log units), BBB (for 182 compounds, R-2 was 0.69 and rmse was 0.87 log units), and Caco-2/MDCK assays (for 165 compounds, R-2 was 0.52 and rmse was 0.89 log units).