苯并呋喃核心抑制剂HCV-796、BMS-929075、MK-8876、化合物2和化合物9B对NS5B聚合酶的各种基因型表现出良好的泛基因型活性。为了阐明它们的作用机制,使用多种分子模拟方法来研究这些抑制剂与GT1a结合的复杂系统,1b,2a,和2b个NS5B聚合酶。计算结果表明,这5种抑制剂不仅能与NS5B聚合酶的palmⅡ亚结构域中的残基相互作用,而且还具有棕榈I亚结构域或棕榈I/III重叠区域中的残基。有趣的是,在C5位置具有较长取代基的抑制剂(BMS-929075、MK-8876、化合物2和化合物9B)与GT1a和2b的NS5B聚合酶的结合与与GT1b和2a的NS5B聚合酶的结合相比表现出不同的结合模式。抑制剂C2位的对氟苯基与结合袋的残基之间的相互作用,以及C5位置的取代基与反向β倍的残基(残基441-456)之间的相互作用,在识别和诱导结合中起关键作用。相关研究可为进一步研究和开发新型抗HCV苯并呋喃核心泛基因型抑制剂提供有价值的信息。
The benzofuran core inhibitors HCV-796, BMS-929075, MK-8876, compound 2, and compound 9B exhibit good pan-genotypic activity against various genotypes of NS5B polymerase. To elucidate their mechanism of action, multiple molecular simulation methods were used to investigate the complex systems of these inhibitors binding to GT1a, 1b, 2a, and 2b NS5B polymerases. The calculation results indicated that these five inhibitors can not only interact with the residues in the palm II subdomain of NS5B polymerase, but also with the residues in the palm I subdomain or the palm I/III overlap region. Interestingly, the binding of inhibitors with longer substituents at the C5 position (BMS-929075, MK-8876, compound 2, and compound 9B) to the GT1a and 2b NS5B polymerases exhibits different binding patterns compared to the binding to the GT1b and 2a NS5B polymerases. The interactions between the para-fluorophenyl groups at the C2 positions of the inhibitors and the residues at the binding pockets, together with the interactions between the substituents at the C5 positions and the residues at the reverse β-fold (residues 441-456), play a key role in recognition and the induction of the binding. The relevant studies could provide valuable information for further research and development of novel anti-HCV benzofuran core pan-genotypic inhibitors.