文献类型：期刊文献

英文题名：Novel Combination Therapy for Heart Failure: Trimebutine-Methoxsalen Identified through Synergistic Network Virtual Screening and Experimental Validation

作者：Huang, Yunyuan[1];Chen, Xin[2];Yang, Jin[3];Yao, Yue[3];Wang, Manjiong[3];Lu, Taotao[3];Li, Xiao[3];Wang, Jiqun[3];Qiao, Sicong[3];Shi, Donglei[4];Li, Xiaokang[3];Li, Jian[3,4];Xu, Yixiang[3]

机构：[1]Cent China Normal Univ, Sch Life Sci, Hubei Key Lab Genet Regulat & Integrat Biol, Wuhan 430079, Hubei, Peoples R China;[2]Jinan Univ, State Key Lab Bioact Mol & Druggabil Assessment, Guangzhou 510632, Peoples R China;[3]East China Univ Sci & Technol, Shanghai Key Lab New Drug Design, Frontiers Sci Ctr Materiobiol & Dynam Chem, Sch Pharm,State Key Lab Bioreactor Engn,Shanghai F, Shanghai 200237, Peoples R China;[4]Hainan Univ, Coll Pharm, Minist Educ, Key Lab Trop Biol Resources, Haikou 570228, Hainan, Peoples R China

年份：2024

卷号：64

期号：18

起止页码：7152

外文期刊名：JOURNAL OF CHEMICAL INFORMATION AND MODELING

收录：;EI(收录号：20243817054885);WOS:【SCI-EXPANDED(收录号:WOS:001310752700001)】；

基金：This work was supported by the National Natural Science Foundation of China (grants 82104068 to Y.H., 22107030 to Y.X., 32121005 to J.L., and 82173689 to X.L.), the National Key Research and Development Program of China (grant 2021YFA0804904 to J.L.), the Shanghai Morning Light Program (grant 20CG36 to Y.X.), the Shanghai Frontier Science Center of Optogenetic Techniques for Cell Metabolism (grant 2021 Sci & Tech 03-28 to J.L.), the Innovative Research Team of High-level Local Universities in Shanghai (grant SHSMU-ZDCX20212702 to J.L.), and the Chinese Special Fund for State Key Laboratory of Bioreactor Engineering (grant 2060204 to J.L.), and financial support for this work was by self-determined research funds of Central China Normal University from the colleges' basic research and operation of Ministry of Education (grant CCNU24ai006 to Y.H.).

语种：英文

外文关键词：Cardiology - Diagnosis - Disease control - Drug therapy

摘要：Combination therapy is increasingly favored by pharmaceutical companies and researchers as an effective way to quickly discover new drugs with excellent efficacy, especially in the treatment of complex diseases. Previously, we successfully developed a computational screening method to identify such combinations, although it fell short in elucidating their synergistic mechanisms. In this work, we have transitioned to a highest single agent (HSA) synergy model for network screening, which streamlines the discovery of promising combinations and facilitates the investigation of their synergistic effects. Through this refined approach, the trimebutine-methoxsalen combination emerged as a promising candidate for heart failure (HF) treatment, exhibiting significant in vitro cardioprotective effects and effectively mitigating isoproterenol (ISO)-induced structural remodeling in the mouse heart. Further mechanistic studies have demonstrated that trimebutine and methoxsalen could synergistically inhibit intracellular calcium overload in myocardial cells and reduce the production of ROS, thus exerting cardioprotective effects. Overall, this study introduces an advanced computational strategy that not only identifies a novel combination therapy against HF but also sheds light on its underlying synergistic mechanisms.