基于BiRNN模型的DPP-4和SGLT-2双靶点抑制剂设计
Design of dual-target inhibitors of DPP-4 and SGLT-2 based on BiRNN model
孙定康 1张鑫磊 2郭凯蕾 3李琦 4梁佳龙 5马丽莎 2林佳艳 2何金穗 3刁春妍 2王育伟 3刘雪英2
作者信息
- 1. 陕西中医药大学 药学院,陕西 咸阳 712046;空军军医大学 药学系 药物化学与药物分析教研室,陕西 西安 710032
- 2. 空军军医大学 药学系 药物化学与药物分析教研室,陕西 西安 710032
- 3. 陕西中医药大学 药学院,陕西 咸阳 712046
- 4. 河南大学 生命科学学院,河南 开封 475004
- 5. 中国人民解放军陆军第九四六医院 医疗保障中心,新疆 伊宁 835000
- 折叠
摘要
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.
Abstract
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.
关键词
糖尿病/SGLT-2/DPP-4抑制剂/分子对接/药效团模型/分子动力学模拟Key words
diabetes/SGLT-2/DPP-4 inhibitors/molecular docking/pharmacophore model/molecular dynamics simulations引用本文复制引用
基金项目
陕西省秦创原"科学家+工程师"队伍建设(2023KXJ-080号)
出版年
2024
NETL
NSTL
万方数据