目的 设计DPP-4和SGLT-2双靶点抑制剂。方法 根据现有的DPP-4和SGLT-2活性化合物训练BiRNN模型，使其生成具有潜在活性的双靶点新分子，并使用已经报道的活性化合物构建HipHop药效团模型，通过药效团模型对新分子进行初筛，然后使用分子对接、分子动力学模拟以及结合自由能计算等方法对初筛小分子进行进一步筛选最终得到候选化合物。结果BiRNN模型生成7 494个新分子，经过虚拟筛选发现化合物NM186、NM21、NM249、NM107是相对理想的DPP-4和SGLT-2双靶点抑制剂。结论NM186、NM21、NM249、NM107可能是一种具有新型结构的DPP-4/SGLT-2双靶点抑制剂，这一研究丰富了DPP-4和SGLT-2双靶点抑制剂的多样性，为其开发提供新的设计思路。

Objective To design a dual-target inhibitor of DPP-4 and SGLT-2. Methods The BiRNN model was trained according to the existing DPP-4 and SGLT-2 active compounds to generate new dual-target molecules with potential activity, and the HipHop pharmacophore model was constructed using the reported active compounds, and the new molecules were pre-screened through the pharmacophore model, and then the small molecules were further screened by molecular docking, molecular dynamics simulation and combined free energy calculation, and the candidate compounds were finally obtained. Results A total of 7 494 new molecules were generated by the BiRNN model, and the compounds NM186, NM21, NM249, and NM107 were found to be relatively ideal dual-target inhibitors of DPP-4 and SGLT-2. Conclusion NM186, NM21, NM249 and NM107 may be dual-target inhibitors of DPP-4/SGLT-2 with novel structures, which enriches the diversity of DPP-4 and SGLT-2 dual-target inhibitors and provides new design ideas for their development.

R914.2

陕西省秦创原“科学家+工程师”队伍建设（2023KXJ-080号）