Structure-affinity relationships of Val-Val and Val-Val-Val stereoisomers with the apical oligopeptide transporter in human intestinal Caco-2 cells
Structure-affinity relationships of Val-Val and Val-Val-Val stereoisomers with the apical oligopeptide transporter in human intestinal Caco-2 cells
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DOI：
10.3109/10611869808997860
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发表时间：
1998-01-01
影响因子：
4.5
通讯作者：
Hidalgo, IJ
中科院分区：
文献类型：
--
作者：
Li, JB;Tamura, K;Hidalgo, IJ
本研究的目的是阐明Val-瓦尔和Val-瓦尔-瓦尔的立体异构体的结构特征，这些立体异构体为人肠Caco-2细胞中的顶端寡肽转运蛋白提供最佳结合亲和力。利用Chem-X分子模拟软件对头孢氨苄和瓦尔立体异构体的三维构象进行了优化。与优化的构象的瓦尔立体异构体的分子特征进行了分析，以确定潜在的关系，其结合亲和力的顶端寡肽转运。对于Val-Val立体异构体，发现N-末端氨基和C-末端羧基之间的距离d（N1-C7）在95%置信水平下与其结合亲和力具有线性关系。对于Val-瓦尔-瓦尔立体异构体，发现三个分子特征与它们的结合亲和力在95%置信水平下具有线性关系。这些功能包括：a）N-末端氨基与C-末端羧基之间的距离d（N1-C11）; B）N-末端氨基与第二个肽键之间的距离？d（N1-N9）;和c）分子偶极矩。对Val-瓦尔-瓦尔立体异构体的所有分子特征进行主成分分析，确定了三个组分，占90%的方差。通过多元线性回归用这三个组分构建的线性模型充分描述了结合亲和力（r（2）= 0.90）。从目前的研究结果表明，N-末端氨基和C-末端羧基之间的距离是重要的Caco-2细胞中的顶端寡肽转运蛋白的相互作用。此外，Val-瓦尔-瓦尔立体异构体的结合亲和力似乎受到其他因素的影响，包括第二个肽键的位置和分子偶极矩。
The objective of this study was to elucidate the structural features of the stereoisomers of Val-Val and Val-Val-Val that afford optimal binding affinity for the apical oligopeptide transporter in human intestinal Caco-2 cells. Three-dimensional conformations of cephalexin and Val stereoisomers were optimized using Chem-X molecular modeling software. Molecular features associated with the optimized conformations of the Val stereoisomers were analyzed to identify potential relationships with their binding affinities for the apical oligopeptide transporter. For Val-Val stereoisomers, the distance between the N-terminal amino group and the C-terminal carboxyl group, d(N1-C7), was found to have a linear relationship with their binding affinities at the 95% confidence level. For Val-Val-Val stereoisomers, three molecular features were found to have linear relationships with their binding affinities at the 95% confidence level. These features included: a) the distance between the N-terminal amino group and the C-terminal carboxyl group, d(N1-C11); b) the distance between the N-terminal amino group and the second peptide bond? d(N1-N9); and c) the molecular dipole moment. Principal component analysis on all molecular features of Val-Val-Val stereoisomers identified three components that accounted for 90% of the variance. A linear model built with these three components by multiple linear regression adequately described the binding affinities (r(2) = 0.90). Results from the current study suggest that the distance between the N-terminal amino group and the C-terminal carboxyl group is important for interaction with the apical oligopeptide transporter in Caco-2 cells. In addition, the binding affinities of the Val-Val-Val stereoisomers appear to be influenced by additional factors, including the position of the second peptide bond and the molecular dipole moment.