电压门控钠通道Nav1.7是目前最具潜力的镇痛药物靶点之一，受生物、医学和制药行业密切关注。由于与其他钠通道亚型的序列相似度较大，现有抑制剂选择性不强，副作用较大，限制了其进一步应用开发。鉴于此，提高Nav1.7抑制剂的选择性仍是当前研究热点和难点。我们前期研究得到了一个Nav1.7抑制剂mHNTX-III, 除Nav1.6以外，对其他钠通道亚型活性较弱，机制研究显示mHNTX-III在Nav1.6和Nav1.7上的作用位点存在差异性。本课题以mHNTX-III为模板，借助计算机辅助设计，基于mHNTX-III与Nav1.7和Nav1.6通道的docking复合物，设计和化学合成一系列突变体，以期获得高活性和专一性的改造分子，并利用疼痛动物模型验证其镇痛活性，为获得高效低毒的新型镇痛药物先导分子奠定基础。

The voltage-gated sodium channel Nav1.7 is currently one of the most promising analgesic targets, and has received close attention from biological, medical and pharmaceutical industries. Due to the large sequence similarity with other sodium channel subtypes, the existing Nav1.7 inhibitors are not selective and have side effects, which limits their further application. In view of this, it is still a hot concept and difficult point in improving the selectivity of Nav1.7 inhibitors. In our previous study, we obtained a Nav1.7 inhibitor mHNTX-III with weak affinify to other subtypes except for Nav1.6 channel, and the mechanism research showed that differences exist in the interaction sites of mHNTX-III on Nav1.6 and Nav1.7. This project uses mHNTX-III as a template to design and chemically synthesize a series of mutants based on the interaction complex of HNTX-III docking with Nav1.7 or Nav1.6 by computer-assisted design in order to obtain highly active and specific inhibitor. Animal pain models were used to evaluate analgesic activity. This study lays a foundation for obtaining high-efficiency and low-toxic lead molecules for novel analgesics.