RNA聚合酶（NS5B）是公认的抗HCV药物作用靶点，目前已经发现的NS5B抑制剂大多是核苷类和作用于变构位点的非核苷类抑制剂。作用于活性位点，与金属离子相互络合的非核苷类抑制剂以及不可逆抑制剂是一类全新作用模式的新型抑制剂，极具潜力，但目前研究的较少。为此，本课题组借助药效团模型和分子对接的虚拟筛选的方法，结合骨架迁跃、电子等排等经典药物设计原理发现了黄酮、芳香二酮（三）四氮唑和喹诺酮三种骨架类型的先导化合物。本项目将在前期研究的基础上，继续采用计算机辅助药物设计与经典药物设计原理相结合的方法，并通过多个生物活性筛选评价体系测试，辅以虚拟点突变、生物点突变、和蛋白质共晶等手段，进一步对先导化合物进行"设计-合成-评价"的循环反馈式结构优化和改造，同时发现新的结构类型的先导化合物，丰富抑制剂的结构多样性，以期最终获得活性高，成药性好的NS5B抑制剂，为研发抗HCV药物打下坚实的基础。

The RNA-dependent RNA polymerase (RdRp) of HCV, also known as protein NS5B, has been recognized as a promising and validated target for HCV therapies. Most of the reported inhibitors of NS5B were nucleoside inhibitors and non-nucleoside inhibitors which bind different allosteric sites. However, due to safety concerns, unfavorable drugabilities and drug-resistance, none of NS5B inhibitors were approved for HCV therapies until now. Different from others, a novel class of non-nucleoside inhibitors, as well as irreversible inhibitors, which interact with the metal ions at the active site were promising candidates for the treatment of HCV in e future. Few study focuses on the irreversible inhibitors. Therefore, our group carried out the research and development of this type of NS5B inhibitors. Three types of novel scaffolds' leading compounds, including flavonoids, aryl diketone tetrazoles and quinolones were identified with anti-HCV activities through the combination of computer aid drug design (CADD) and classical drug design strategies, such as pharmacophore based virtual screening, molecular docking, scaffold hopping, bioisosteres and so on. The activities and drug abilities of our leading compounds need further optimization. Hence, in this study, the combination of computer aid drug design (CADD) and classical drugdesign strategies were employed in the following drug design. Through biological activity assay，virtual mutagenesis, site mutagenesis and cocrystallization, leading compounds were further optimized in a circular feedback model of "design-synthesis-evaluation". Meanwhile, more leading compounds with novel structures would be discovered and the diversity of active scaffold would be enriched in our research. We hope that more active and more drugable NS5B inhibitors would be identified and our work would construct a solid foundation in the discovery of novel HCV therapies.