Rapid Repurposing of Novel Combination Drugs for the Treatment of Heart Failure via a Computationally Guided Network Screening Approach

Combination drugs, characterized
by high efficacy and few side
effects, have received extensive attention from pharmaceutical companies
and researchers for the treatment of complex diseases such as heart
failure (HF). Traditional combination drug discovery depends on large-scale
high-throughput experimental approaches that are time-consuming and
costly. Herein we developed a novel, rapid, and potentially universal
computer-guided combination drug-network-screening approach based
on a set of databases and web services that are easy for individuals
to obtain and operate, and we discovered for the first time that the
menthol–allethrin combination screened by this approach exhibited
a significant synergistic cardioprotective effect in vitro. Further mechanistic studies indicated that allethrin and menthol
could synergistically block calcium channels. Allethrin bound to the
central cavity of the voltage-dependent L-type calcium channel subunit
alpha-1S (CACNA1S) lead to a conformational change in an allosteric
site of CACNA1S, thereby enhancing the binding of menthol to this
allosteric site. In summary, we reported a potentially universal computational
approach to combination drug screening that has been used to discover
a new combination of menthol–allethrin against HF in
vitro, providing a new synergistic mechanism and prospective
agent for HF treatment.