An Jianghong, Lee Davy C W, Law Anna H Y, Yang Cindy L H, Poon Leo L M, Lau Allan S Y, Jones Steven J M
British Columbia Cancer Agency Genome Sciences Centre, 675 West 10th Avenue, Vancouver, British Columbia V5Z 4S6, Canada.
J Med Chem. 2009 May 14;52(9):2667-72. doi: 10.1021/jm800455g.
Computational molecular docking provides an efficient and innovative approach to examine small molecule and protein interactions. We have utilized this method to identify potential inhibitors of the H5N1 neuraminidase protein. Of the 20 compounds tested, 4-(4-((3-(2-amino-4-hydroxy-6-methyl-5-pyrimidinyl)propyl)amino)phenyl)-1-chloro-3-buten-2-one (1) (NSC89853) demonstrated the ability to inhibit viral replication at a level comparable to the known neuraminidase inhibitor oseltamivir. Compound 1 demonstrated efficacy across a number of cell-lines assays and in both the H1N1 and H5N1 viruses. The predicted binding of 1 to the known H5N1 neuraminidase structure indicates a binding interface largely nonoverlapping with that of oseltamivir or another neuraminidase inhibitor zanamivir. These results indicate that 1 or similar molecules would remain effective in the presence of virus mutations conferring resistance to either oseltamivir or zanamivir and also vice versa.
计算分子对接为研究小分子与蛋白质的相互作用提供了一种高效且创新的方法。我们利用这种方法来鉴定H5N1神经氨酸酶蛋白的潜在抑制剂。在测试的20种化合物中，4-(4-((3-(2-氨基-4-羟基-6-甲基-5-嘧啶基)丙基)氨基)苯基)-1-氯-3-丁烯-2-酮（1）（NSC89853）表现出抑制病毒复制的能力，其水平与已知的神经氨酸酶抑制剂奥司他韦相当。化合物1在多种细胞系试验以及H1N1和H5N1病毒中均显示出疗效。预测1与已知的H5N1神经氨酸酶结构的结合表明，其结合界面与奥司他韦或另一种神经氨酸酶抑制剂扎那米韦的结合界面基本不重叠。这些结果表明，在存在对奥司他韦或扎那米韦产生耐药性的病毒突变的情况下，1或类似分子仍将有效，反之亦然。
