Li Guo, Haney Kendra M, Kellogg Glen E, Zhang Yan
Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia 23298-0540, USA.
J Chem Inf Model. 2009 Jan;49(1):120-32. doi: 10.1021/ci800356a.
Anibamine, a novel pyridine quaternary alkaloid recently isolated from Aniba sp., has been found to effectively bind to the chemokine receptor CCR5 with an IC(50) at 1 microM in competition with (125)I-gp120, an HIV viral envelope protein binding to CCR5 with high affinity. Since CCR5, a G-protein-coupled receptor, is an essential coreceptor for the human immunodeficiency virus type I (HIV-1) entry to host cells, a CCR5 antagonist that inhibits the cellular entry of HIV-1 provides a new therapy choice for the treatment of HIV. Anibamine provides a novel structural skeleton that is remarkably different from all lead compounds previously identified as CCR5 antagonists. Here, we report comparative docking studies of anibamine with several other known CCR5 antagonists in two CCR5 homology models built based on the crystal structures of bovine rhodopsin and human beta(2)-adrenergic receptor. The binding pocket of anibamine has some common features shared with other high affinity CCR5 antagonists, suggesting that they may bind in similar binding sites and/or modes. At the same time, several unique binding features of anibamine were identified, and it will likely prove beneficial in future molecular design of novel CCR5 antagonists based on the anibamine scaffold.
阿尼巴明是最近从阿尼巴属植物中分离出的一种新型吡啶季铵生物碱，已发现它能与趋化因子受体CCR5有效结合，在与125I-gp120竞争时的半数抑制浓度（IC50）为1微摩尔，125I-gp120是一种能与CCR5高亲和力结合的HIV病毒包膜蛋白。由于CCR5作为一种G蛋白偶联受体，是I型人类免疫缺陷病毒（HIV-1）进入宿主细胞所必需的共受体，一种抑制HIV-1细胞进入的CCR5拮抗剂为治疗HIV提供了一种新的治疗选择。阿尼巴明提供了一种与先前鉴定为CCR5拮抗剂的所有先导化合物显著不同的新型结构骨架。在此，我们报告了在基于牛视紫红质和人β2-肾上腺素能受体晶体结构构建的两个CCR5同源模型中，阿尼巴明与其他几种已知CCR5拮抗剂的比较对接研究。阿尼巴明的结合口袋与其他高亲和力CCR5拮抗剂有一些共同特征，表明它们可能在相似的结合位点和/或模式下结合。同时，鉴定出了阿尼巴明的几个独特结合特征，这可能在未来基于阿尼巴明支架的新型CCR5拮抗剂分子设计中被证明是有益的。
