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International Journal of Molecular Sciences

International Journal of Molecular Sciences

IF: 5.6
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Discovery of TRPV4-Targeting Small Molecules with Anti-Influenza Effects Through Machine Learning and Experimental Validation

Published:6 February 2025 DOI: 10.3390/ijms26031381 PMID: 39941149
Yan Sun,?Jiajing Wu,?Beilei Shen,?Hengzheng Yang,?Huizi Cui,?Weiwei Han,?Rongbo Luo,?Shijun Zhang,?He Li,?Bingshuo Qian,?Lingjun Fan,?Junkui Zhang,?Tiecheng Wang,?Xianzhu Xia,?Fang Yan,?Yuwei Gao

Abstract

Transient receptor potential vanilloid 4 (TRPV4) is a calcium-permeable cation channel critical for maintaining intracellular Ca2+ homeostasis and is essential in regulating immune responses, metabolic processes, and signal transduction. Recent studies have shown that TRPV4 activation enhances influenza A virus infection, promoting viral replication and transmission. However, there has been limited exploration of antiviral drugs targeting the TRPV4 channel. In this study, we developed the first machine learning model specifically designed to predict TRPV4 inhibitory small molecules, providing a novel approach for rapidly identifying repurposed drugs with potential antiviral effects. Our approach integrated machine learning, virtual screening, data analysis, and experimental validation to efficiently screen and evaluate candidate molecules. For high-throughput virtual screening, we employed computational methods to screen open-source molecular databases targeting the TRPV4 receptor protein. The virtual screening results were ranked based on predicted scores from our optimized model and binding energy, allowing us to prioritize potential inhibitors. Fifteen small-molecule drugs were selected for further in vitro and in vivo antiviral testing against influenza. Notably, glecaprevir and everolimus demonstrated significant inhibitory effects on the influenza virus, markedly improving survival rates in influenza-infected mice (protection rates of 80% and 100%, respectively). We also validated the mechanisms by which these drugs interact with the TRPV4 channel. In summary, our study presents the first predictive model for identifying TRPV4 inhibitors, underscoring TRPV4 inhibition as a promising strategy for antiviral drug development against influenza. This pioneering approach lays the groundwork for future clinical research targeting the TRPV4 channel in antiviral therapies.

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Materials
Procduct Name CAS Molecular Formula Supplier Price
Acarbose 56180-94-0 C25H43NO18 760 suppliers $6.00-$2245.70
Acarbose 56180-94-0 C25H43NO18 760 suppliers $6.00-$2245.70
Acarbose 56180-94-0 C25H43NO18 760 suppliers $6.00-$2245.70
Acarbose 56180-94-0 C25H43NO18 760 suppliers $6.00-$2245.70
Everolimus 159351-69-6 C53H83NO14 628 suppliers $8.00-$3165.00
Everolimus 159351-69-6 C53H83NO14 628 suppliers $8.00-$3165.00
Everolimus 159351-69-6 C53H83NO14 628 suppliers $8.00-$3165.00
Everolimus 159351-69-6 C53H83NO14 628 suppliers $8.00-$3165.00
Troxerutin 7085-55-4 C33H42O19 511 suppliers $5.00-$1820.00
Troxerutin 7085-55-4 C33H42O19 511 suppliers $5.00-$1820.00

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