Department of Microbiology and Immunology of Basical Medicine of Guangdong Medical University, Dongguan, Guangdong Province, China.
Department of Respiratory diseases of Shenzhen Children's Hospital, Shenzhen, Guangdong Province, China.
PLoS Comput Biol. 2022 Jul 28;18(7):e1010343. doi: 10.1371/journal.pcbi.1010343. eCollection 2022 Jul.
Oseltamivir is a widely used influenza virus neuraminidase (NA) inhibitor that prevents the release of new virus particles from host cells. However, oseltamivir-resistant strains have emerged, but effective drugs against them have not yet been developed. Elucidating the binding mechanisms between NA and oseltamivir may provide valuable information for the design of new drugs against NA mutants resistant to oseltamivir. Here, we conducted large-scale (353.4 μs) free-binding molecular dynamics simulations, together with a Markov State Model and an importance-sampling algorithm, to reveal the binding process of oseltamivir and NA. Ten metastable states and five major binding pathways were identified that validated and complemented previously discovered binding pathways, including the hypothesis that oseltamivir can be transferred from the secondary sialic acid binding site to the catalytic site. The discovery of multiple new metastable states, especially the stable bound state containing a water-mediated hydrogen bond between Arg118 and oseltamivir, may provide new insights into the improvement of NA inhibitors. We anticipated the findings presented here will facilitate the development of drugs capable of combating NA mutations.
奥司他韦是一种广泛应用于流感病毒神经氨酸酶（NA）抑制剂，可防止新病毒颗粒从宿主细胞中释放。然而，已经出现了对奥司他韦耐药的菌株，但针对这些菌株的有效药物尚未开发出来。阐明 NA 与奥司他韦之间的结合机制可为设计针对奥司他韦耐药 NA 突变体的新药提供有价值的信息。在这里，我们进行了大规模（353.4 μs）的自由结合分子动力学模拟，结合马尔可夫状态模型和重要性抽样算法，揭示了奥司他韦和 NA 的结合过程。确定了十个亚稳态和五个主要结合途径，验证和补充了以前发现的结合途径，包括奥司他韦可以从次要唾液酸结合位点转移到催化位点的假说。多个新的亚稳态的发现，特别是包含 Arg118 与奥司他韦之间的水介导氢键的稳定结合态，可能为改进 NA 抑制剂提供新的见解。我们预计这里提出的发现将有助于开发能够对抗 NA 突变的药物。
