Novel Combination Therapy for Heart Failure: Trimebutine–Methoxsalen Identified through Synergistic Network Virtual Screening and Experimental Validation

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.