Simulation-based cheminformatic analysis of organelle-targeted molecules: lysosomotropic monobasic amines.
Simulation-based cheminformatic analysis of organelle-targeted molecules: lysosomotropic monobasic amines.
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DOI：
10.1007/s10822-008-9194-7
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发表时间：
2008-09
影响因子：
3.5
通讯作者：
Rosania, Gus R.
中科院分区：
文献类型：
--
作者：
Zhang, Xinyuan;Zheng, Nan;Rosania, Gus R.
关键词：
基于细胞的分子运输模拟正在被开发，以促进小药物样分子虚拟文库的探索性化学分析。为此，单细胞的数学模型是由捕获小分子跨膜运输的方程建立起来的。反过来，小分子的物理化学性质可以作为模拟细胞内药物随时间分布的输入。在这里，通过调整数学方程和生物学参数以模拟血液中的白细胞，进行模拟以分析在均匀的细胞外药物浓度存在的情况下，靶细胞的溶酶体、线粒体和细胞质中小分子的稳态相对积累。同样，通过设置模拟肠上皮细胞的方程和参数，还进行了模拟，以分析在存在根尖到基底侧浓度梯度的情况下，该非靶细胞的稳态、相对分布和跨细胞通透性。利用从科学文献中收集的99种单碱胺的测试集，模拟结果有助于分析这些分子的化学多样性与其细胞内分布之间的关系。本文的在线版本（doi:10.1007/s10822-008-9194-7）包含补充材料，仅供授权用户使用。
Cell-based molecular transport simulations are being developed to facilitate exploratory cheminformatic analysis of virtual libraries of small drug-like molecules. For this purpose, mathematical models of single cells are built from equations capturing the transport of small molecules across membranes. In turn, physicochemical properties of small molecules can be used as input to simulate intracellular drug distribution, through time. Here, with mathematical equations and biological parameters adjusted so as to mimic a leukocyte in the blood, simulations were performed to analyze steady state, relative accumulation of small molecules in lysosomes, mitochondria, and cytosol of this target cell, in the presence of a homogenous extracellular drug concentration. Similarly, with equations and parameters set to mimic an intestinal epithelial cell, simulations were also performed to analyze steady state, relative distribution and transcellular permeability in this non-target cell, in the presence of an apical-to-basolateral concentration gradient. With a test set of ninety-nine monobasic amines gathered from the scientific literature, simulation results helped analyze relationships between the chemical diversity of these molecules and their intracellular distributions. The online version of this article (doi:10.1007/s10822-008-9194-7) contains supplementary material, which is available to authorized users.
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