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

Abstract

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.

Identification of Guaifenesin–Andrographolide as a Novel Combinatorial Drug Therapy for Epilepsy Using Network Virtual Screening and Experimental Validation

“…Network-Based Virtual Screening. The screening workflow of a combination drug against epilepsy was performed as described in our previous work 12 (Figure 1). In this work, we used approved drugs in our in-house drug library and those in the DrugBank database; overall, information about 2308 drugs with 2989 targets was obtained from DrugBank, Binding DB, and PubChem.…”

“…Virtual screening of combination drugs was performed following a previously described protocol . We collected information about the approved drugs from the DrugBank database and our in-house drug library.…”

“…Virtual screening of combination drugs was performed following a previously described protocol. 12 We collected information about the approved drugs from the DrugBank database and our in-house drug library. Information about the targets of these drugs was collected from DrugBank, 33 Binding DB, 34 and PubChem.…”

“…Computational screening for combination drugs is usually mechanism-driven and is recognized as a useful approach for the development of novel combinatorial drug therapies for diseases with complex pathological mechanisms. In our previous work, 12 we established a potentially universal computational screening approach for combination drugs and first found that menthol, allethrin, and their combination exhibit significant cardioprotective properties in vitro. Furthermore, the novel synergistic mechanism of menthol−allethrin against heart failure in vitro was clearly illustrated.…”

Repurposing drugs to treat cardiovascular disease in the era of precision medicine

“…Analyses can take the form of in vitro screening of drug targets cross-referenced to known signalling pathways contributing to disease. This approach was used to identify the combination of allethrin and menthol as a potential therapy for heart failure, a finding that has been validated in vitro 23 .…”