Molecular interactions of CCR5 with major classes of small-molecule anti-HIV CCR5 antagonists
Molecular interactions of CCR5 with major classes of small-molecule anti-HIV CCR5 antagonists
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DOI：
10.1124/mol.107.042101
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发表时间：
2008-03-01
影响因子：
3.6
通讯作者：
Dioszegi, Marianna
中科院分区：
文献类型：
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作者：
Kondru, Rama;Zhang, Jun;Dioszegi, Marianna
CCR5不仅是白细胞活化和动员的重要受体，也是人类免疫缺陷病毒(HIV)的重要辅助受体。已有大量的小分子CCR5拮抗剂被报道，它们在阻断趋化因子功能和HIV侵入方面显示出强大的活性。为了方便下一代CCR5拮抗剂的设计和开发，利用定点突变和CCR5同源模型建立了主要类别CCR5拮抗剂的对接模型。五个临床候选药物：马拉韦罗、维昔洛克、阿普拉韦罗、TAK-779和TAK-220被用来确定CCR5中结合口袋的性质。尽管这五种拮抗剂在结构、形状和静电势上有很大的不同，但它们能够放在CCR5的跨膜(TM)结构域形成的同一结合口袋中。值得注意的是，每个拮抗剂都显示出与口袋内氨基酸的独特相互作用。除TAK-779外，所有拮抗剂均通过中枢碱性氮与TM7中的Glu283发生强相互作用。CCR5的完全映射结合口袋正被用于基于结构的设计和领先优化新型抗HIV CCR5抑制剂，具有更好的效力和更好的耐药性。
In addition to being an important receptor in leukocyte activation and mobilization, CCR5 is the essential coreceptor for human immunodeficiency virus (HIV). A large number of small-molecule CCR5 antagonists have been reported that show potent activities in blocking chemokine function and HIV entry. To facilitate the design and development of next generation CCR5 antagonists, docking models for major classes of CCR5 antagonists were created by using site-directed mutagenesis and CCR5 homology modeling. Five clinical candidates: maraviroc, vicriviroc, aplaviroc, TAK-779, and TAK-220 were used to establish the nature of the binding pocket in CCR5. Although the five antagonists are very different in structure, shape, and electrostatic potential, they were able to fit in the same binding pocket formed by the transmembrane (TM) domains of CCR5. It is noteworthy that each antagonist displayed a unique interaction profile with amino acids lining the pocket. Except for TAK-779, all antagonists showed strong interaction with Glu283 in TM 7 via their central basic nitrogen. The fully mapped binding pocket of CCR5 is being used for structure-based design and lead optimization of novel anti-HIV CCR5 inhibitors with improved potency and better resistance profile.