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

作　　者：孙定康 张鑫磊 郭凯蕾 李琦 梁佳龙 马丽莎 林佳艳 何金穗 刁春妍 王育伟 刘雪英 SUN Dingkang;ZHANG Xinlei;GUO Kailei;LI Qi;LIANG Jialong;MA Lisha;LIN Jiayan;HE Jinsui;DIAO Chunyan;WANG Yuwei;LIU Xueying(Department of Pharmacy,Shaanxi University of Traditional Chinese Medicine,Xianyang 712046,China;Department of Medicinal Chemistry,School of Pharmacy,Air Force Medical University,Xi’an 710032,China;College of Life Sciences,Henan University,Kaifeng 475004,China;No.946 Hospital of the People’s Liberation Army Ground Force,Yining 835000,China)

机构地区：[1]陕西中医药大学药学院,陕西咸阳712046 [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]河南大学生命科学学院,河南开封475004 [4]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

出　　处：《现代药物与临床》2024年第7期1689-1703,共15页Drugs & Clinic

基　　金：陕西省秦创原“科学家+工程师”队伍建设(2023KXJ-080号)。

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。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 7494 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 

分 类 号：R914.2[医药卫生—药物化学]