本研究为克服上市药物奥司他韦和帕拉米韦易产生耐药性、口服生物利用度低等诸多缺点，在前期流感病毒抑制剂的研究基础上（J Med Chem. 2014, 57, 8445），以NA活性中心邻近区域新发现的150-腔和430-腔为新结合位点，运用“多位点结合”策略，对奥司他韦和帕拉米韦进行优化改造。通过在两个先导化合物的氨基和羧基上引入额外基团，使改造后的侧链可以伸入空腔中，并与其中的关键氨基酸残基形成“附加”作用力，以达到与 NA活性中心、150-腔和430-腔形成“多位点结合”的目的，从而提高其抑制活性和抗耐药性并改善药代动力学性质。由此，我们设计了三类“多位点结合”型奥司他韦类和帕拉米韦类衍生物，并对此类衍生物进行体内外抗流感病毒活性测试和初步的类药性评价，以期发现高效、抗耐药性和药代动力学性质良好的具有临床应用前景的新型神经氨酸酶抑制剂，为开发具有自主知识产权的抗流感药物奠定基础。

The recently discovered 150-cavity and 430-cavity adjacent to the enzymatic active site of influenza A neuraminidase (NA) have been considered as important starting points for the design of next-generation NA inhibitors. Close examination of the crystal structure of oseltamivir carboxylate and peramivir bound with NA revealed that the amino (guanidino) and carboxyl groups of oseltamivir carboxylate or peramivir are well exposed toward these newly discovered cavities and could serve as the potential modification sites in the design of specific inhibitors to improve the antiviral efficacy, drug resistance profiles and pharmacokinetic properties of the approved neuraminidase inhibitors. As a continuation of our efforts to discover and novel neuraminidase inhibitors (J Med Chem. 2014, 57, 8445), based on the above analysis and “Multiple-Ssites Binding” concept, in this project, our proposed strategy is to extend the structures of existing inhibitors by attaching additional groups of suitable shape, size, and hydrophobicity to fill the newly found cavity. Specifically, by introducing these diverse substituents to the scaffolds of oseltamivir carboxylate and peramivir, virtual molecular library was constructed. The hierarchical multiple-filter virtual database searching strategy is utilized to vitually srceen the designed molecule liberary by scoring their binding affinity, multiple drug-like profiles, and their ADMET properties. The top-ranking compounds will be selected to be synthesized and evaluated for their in vitro anti-influenza virus activities, neuraminidase-inhibitory activities and preliminary druggability evaluation, with the expectation of obtaining the next generation of “Multiple-Sites Binding”-typed influenza virus inhibitors with improved resistance profiles and favorable druggability.