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 expe...

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Bibliographic Details
Published in:Journal of chemical information and modeling 2022-11, Vol.62 (21), p.5223-5232
Main Authors: Huang, Yunyuan, Wang, Jiqun, Liu, Jiaqi, Shi, Donglei, Li, Xiaokang, Wang, Manjiong, Lu, Taotao, Jiang, Bei, Xia, Conglong, Lin, Houwen, Xu, Yixiang, Li, Jian
Format: Article
Language:English
Subjects:
Allethrins
Calcium
Computational Biochemistry
Drug Repositioning
Drugs
Heart failure
Heart Failure - drug therapy
Humans
Menthol
Menthol - pharmacology
Prospective Studies
Screening
Side effects
Web services
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Summary: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.
ISSN:1549-9596
1549-960X
DOI:10.1021/acs.jcim.1c00132