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Novel Combination Therapy for Heart Failure: Trimebutine–Methoxsalen Identified through Synergistic Network Virtual Screening and Experimental Validation
Journal of Chemical Information and Modeling ( IF 5.6 ) Pub Date : 2024-09-11 , DOI: 10.1021/acs.jcim.4c00670 Yunyuan Huang 1 , Xin Chen 2 , Jin Yang 3 , Yue Yao 3 , Manjiong Wang 3 , Taotao Lu 3 , Xiao Li 3 , Jiqun Wang 3 , Sicong Qiao 3 , Donglei Shi 4 , Xiaokang Li 3 , Jian Li 3, 4, 5 , Yixiang Xu 3
Journal of Chemical Information and Modeling ( IF 5.6 ) Pub Date : 2024-09-11 , DOI: 10.1021/acs.jcim.4c00670 Yunyuan Huang 1 , Xin Chen 2 , Jin Yang 3 , Yue Yao 3 , Manjiong Wang 3 , Taotao Lu 3 , Xiao Li 3 , Jiqun Wang 3 , Sicong Qiao 3 , Donglei Shi 4 , Xiaokang Li 3 , Jian Li 3, 4, 5 , Yixiang Xu 3
Affiliation
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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.
中文翻译：
心力衰竭的新型联合疗法：通过协同网络虚拟筛选和实验验证确定曲美布汀-甲氧沙林
联合疗法作为快速发现疗效优异的新药的有效途径，特别是在治疗复杂疾病方面越来越受到制药公司和研究人员的青睐。此前，我们成功开发了一种计算筛选方法来识别此类组合，尽管它未能阐明其协同机制。在这项工作中，我们已经过渡到用于网络筛选的最高单剂（HSA）协同模型，该模型简化了有希望的组合的发现并促进了其协同效应的研究。通过这种改进的方法，曲美布汀-甲氧沙林组合成为心力衰竭（HF）治疗的有前途的候选药物，表现出显着的体外心脏保护作用，并有效减轻异丙肾上腺素（ISO）诱导的小鼠心脏结构重塑。进一步的机理研究表明，曲美布汀和甲氧沙林可以协同抑制心肌细胞内钙超载，减少ROS的产生，从而发挥心脏保护作用。总的来说，这项研究引入了一种先进的计算策略，不仅确定了一种针对心力衰竭的新型联合疗法，而且还揭示了其潜在的协同机制。
更新日期：2024-09-11
中文翻译：
心力衰竭的新型联合疗法：通过协同网络虚拟筛选和实验验证确定曲美布汀-甲氧沙林
联合疗法作为快速发现疗效优异的新药的有效途径，特别是在治疗复杂疾病方面越来越受到制药公司和研究人员的青睐。此前，我们成功开发了一种计算筛选方法来识别此类组合，尽管它未能阐明其协同机制。在这项工作中，我们已经过渡到用于网络筛选的最高单剂（HSA）协同模型，该模型简化了有希望的组合的发现并促进了其协同效应的研究。通过这种改进的方法，曲美布汀-甲氧沙林组合成为心力衰竭（HF）治疗的有前途的候选药物，表现出显着的体外心脏保护作用，并有效减轻异丙肾上腺素（ISO）诱导的小鼠心脏结构重塑。进一步的机理研究表明，曲美布汀和甲氧沙林可以协同抑制心肌细胞内钙超载，减少ROS的产生，从而发挥心脏保护作用。总的来说，这项研究引入了一种先进的计算策略，不仅确定了一种针对心力衰竭的新型联合疗法，而且还揭示了其潜在的协同机制。
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