Characterization of two pharmacophores on the multidrug transporter P-glycoprotein
Characterization of two pharmacophores on the multidrug transporter P-glycoprotein
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DOI：
10.1124/mol.62.6.1288
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发表时间：
2002-12-01
影响因子：
3.6
通讯作者：
Orlowski, S
中科院分区：
文献类型：
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作者：
Garrigues, A;Loiseau, N;Orlowski, S
多药转运蛋白P-糖蛋白是一种质膜蛋白，参与细胞和组织的解毒和多药耐药（MDR）表型。它积极地从细胞中排出许多细胞毒性分子，所有分子都是两亲性的，但化学上不相关。我们调查的分子特性参与的结合选择性的P-糖蛋白的分子建模方法，使用各种基板结合酶的研究，使用这些基板和天然膜囊泡制备的MDR细胞。我们确定的亲和力和相互关系的变化，在P-糖蛋白ATP酶活性诱导的一系列环肽和肽样化合物，单独使用或组合。这一系列的分子的疏水性和极性表面的分子内分布的建模使得有可能将这些表面元素的一些。这些分子排列与观察到的相互排斥的P-糖蛋白结合。这导致了两个不同的，但部分重叠的药效团的表征。在这些药效团中的每一个上，配体彼此竞争。典型的MDR相关分子维拉帕米、环孢菌素A和放线菌素D与药效团1结合，而长春碱与药效团2结合。因此，P-糖蛋白的多特异性结合口袋可以被看作是彼此靠近的位点，其根据配体的疏水性和极性元件而不是其化学基序的分布来结合配体。两个药效团的存在增加了多种化学结构识别的可能性。配体的大小影响其与其他配体竞争结合P-糖蛋白的能力。
The multidrug transporter P-glycoprotein is a plasma membrane protein involved in cell and tissue detoxification and the multidrug resistance (MDR) phenotype. It actively expels from cells a number of cytotoxic molecules, all amphiphilic but chemically unrelated. We investigated the molecular characteristics involved in the binding selectivity of P-glycoprotein by means of a molecular modeling approach using various substrates combined with an enzymological study using these substrates and native membrane vesicles prepared from MDR cells. We determined affinities and mutual relationships from the changes in P-glycoprotein ATPase activity induced by a series of cyclic peptides and peptide-like compounds, used alone or in combination. Modeling of the intramolecular distribution of the hydrophobic and polar surfaces of this series of molecules made it possible to superimpose some of these surface elements. These molecular alignments were correlated with the observed mutual exclusions for binding on P-glycoprotein. This led to the characterization of two different, but partially overlapping, pharmacophores. On each of these pharmacophores, the ligands compete with each other. The typical MDR-associated molecules, verapamil, cyclosporin A, and actinomycin D, bound to pharmacophore 1, whereas vinblastine bound to pharmacophore 2. Thus, the multispecific binding pocket of P-glycoprotein can be seen as sites, located near one another, that bind ligands according to the distribution of their hydrophobic and polar elements rather than their chemical motifs. The existence of two pharmacophores increases the possibilities for multiple chemical structure recognition. The size of the ligands affects their ability to compete with other ligands for binding to P-glycoprotein.