The RNA-dependent RNA polymerase (RdRp) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a promising drug target for coronavirus disease 2019 (COVID-19) because it plays the most important role in the replication of the RNA genome. Nucleotide analogs such as remdesivir and favipiravir are thought to interfere with the RNA replication by RdRp. More specifically, they are expected to compete with nucleoside triphosphates, such as ATP. However, the process in which these drug molecules and nucleoside triphosphates are taken up by RdRp remains unknown. In this study, we performed all-atom molecular dynamics simulations to clarify the recognition mechanism of RdRp for these drug molecules and ATP that were at a distance. The ligand recognition ability of RdRp decreased in the order of remdesivir, favipiravir, and ATP. We also identified six recognition paths. Three of them were commonly found in all ligands, and the remaining three paths were ligand-dependent ones. In the common two paths, it was observed that the multiple lysine residues of RdRp carried the ligands to the binding site like a “bucket brigade.” In the remaining common path, the ligands directly reached the binding site. Our findings contribute to the understanding of the efficient ligand recognition by RdRp at the atomic level.

严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 的 RNA 依赖性 RNA 聚合酶 (RdRp) 是 2019 年冠状病毒病 (COVID-19) 有前景的药物靶点，因为它在 RNA 复制中发挥着最重要的作用基因组。瑞德西韦和法匹拉韦等核苷酸类似物被认为可干扰 RdRp 的 RNA 复制。更具体地说，它们有望与三磷酸核苷（例如 ATP）竞争。然而，这些药物分子和三磷酸核苷被 RdRp 吸收的过程仍然未知。在本研究中，我们进行了全原子分子动力学模拟，以阐明RdRp对这些远距离药物分子和ATP的识别机制。RdRp的配体识别能力按瑞德西韦、法匹拉韦、ATP的顺序降低。我们还确定了六个识别路径。其中三种在所有配体中都很常见，其余三种路径是配体依赖性路径。在常见的两条路径中，观察到RdRp的多个赖氨酸残基像“水桶旅”一样将配体携带到结合位点。在剩下的共同路径中，配体直接到达结合位点。我们的研究结果有助于理解 RdRp 在原子水平上的有效配体识别。