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当代肿瘤药物靶点

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ISSN (Print): 1568-0096
ISSN (Online): 1873-5576

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Research Article

利用网格独立描述（GRIND）分析和SAR引导分子对接研究来探讨耐多药转运体ABCB1和ABCG2抑制剂选择性分布

作者: Talha Shafi, Ishrat Jabeen.

卷 17, 期 2, 2017

页: [177 - 190] 页: 14

弟呕挨: 10.2174/1568009616666160901094140

价格: $65

摘要

背景：结合ATP盒（ABC）转运蛋白，P-糖蛋白（P-gp，ABCB1）和乳腺癌耐药蛋白（BCRP/ABCG2）是药代动力学的主要决定因素，药物安全性和有效性从而调节广泛的内源性物质穿过细胞膜。这些转运蛋白在多种肿瘤中过度表达也与多药耐药（MDR）的发展有关，因此阻碍了癌症化疗的成功。这些外排转运蛋白的调节器与化疗药物联合可以提高抗癌药物有效胞内浓度。然而，由于广泛的和重叠的底物以及ABCB1、ABCG2调制器的特异性只产生毒性、有害的药物相互作用并因此导致药物治疗的后期失败。 目的：在研究是目标是确定ABCB1、ABCG2转运功能的选择性抑制的具体的3D结构要求。 方法：使用其最可能的结合构象从分子对接协议获取，网格独立分子描述符（GRIND）模型的选择性抑制剂的两个转运已得到开发。 结果：我们的研究结果表明，分子的形状和不同的氢键模式对ABCB1和ABCG2的药物的选择性作用起主导作用。此外，不同药效的不同距离以分子空间热点为特征，为两种转运提供了一个强大的选择性基础。研究结果也表明，ABCG2的选择性调节剂中两个氢键供体的存在的距离为8.4-8.8Å。 结论：我们的研究结果表明，MDR调节剂分子的形状随着氢键以及三维模式在确定两个靶点的选择性上起关键作用。

关键词: 多药耐药基因1（MDR1），乳腺癌耐药蛋白（BCRP）多药耐药，网格独立描述，分子对接，选择性分析

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