Identification of Potent Chloride Intracellular Channel Protein 1 Inhibitors from Traditional Chinese Medicine
Wei Wang1,2,3, Minghui Wan4,5, Dongjiang Liao2,3
1Department of Thoracic Surgery, First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China.
Abstract:
Chloride intracellular channel 1 (CLIC1) is involved in the development of most aggressive human tumors, including gastric, colon, lung, liver, and glioblastoma cancers. It has become an attractive new therapeutic target for several types of cancer. In this work, we aim to identify natural products as potent CLIC1 inhibitors from Traditional Chinese Medicine (TCM) database using structure-based virtual screening and molecular dynamics (MD) simulation. First, structure-based docking was employed to screen the refined TCM database and the top 500 TCM compounds were obtained and reranked by X-Score. Then, 30 potent hits were achieved from the top 500 TCM compounds using cluster and ligand-protein interaction analysis. Finally, MD simulation was employed to validate the stability of interactions between each hit and CLIC1 protein from docking simulation, and Molecular Mechanics/Generalized Born Surface Area (MM-GBSA) analysis was used to refine the virtual hits. Six TCM compounds with top MM-GBSA scores and ideal-binding models were confirmed as the final hits. Our study provides information about the interaction between TCM compounds and CLIC1 protein, which may be helpful for further experimental investigations. In addition, the top 6 natural products structural scaffolds could serve as building blocks in designing drug-like molecules for CLIC1 inhibition.
Insights
Researchers identified six natural products from Traditional Chinese Medicine as potential inhibitors of Chloride intracellular channel 1 (CLIC1), a target in aggressive cancers. These compounds show promise for developing new CLIC1-targeted cancer therapies.
Area of Science:
- Computational chemistry and pharmacology
- Natural product drug discovery
- Oncology and molecular targeting
Background:
- Chloride intracellular channel 1 (CLIC1) is implicated in aggressive human cancers, including gastric, colon, lung, liver, and glioblastoma.
- CLIC1 represents a promising therapeutic target for various cancer types.
- Identifying novel, effective inhibitors is crucial for advancing cancer treatment strategies.
Purpose of the Study:
- To identify potent CLIC1 inhibitors from the Traditional Chinese Medicine (TCM) database.
- To utilize structure-based virtual screening and molecular dynamics (MD) simulations for natural product discovery.
- To provide potential lead compounds for the development of CLIC1-targeted cancer therapeutics.
Main Methods:
- Structure-based docking was performed on a refined TCM database.
- Compound ranking using X-Score, followed by cluster and ligand-protein interaction analysis to select potent hits.
- Molecular dynamics (MD) simulations and MM-GBSA analysis were used to validate and refine binding interactions.
Main Results:
- An initial screening yielded 500 compounds, refined to 30 potent hits.
- Molecular dynamics and MM-GBSA analysis identified six TCM compounds with favorable binding to CLIC1.
- The study elucidated the interaction patterns between selected TCM compounds and the CLIC1 protein.
Conclusions:
- Six natural products from TCM were identified as potential CLIC1 inhibitors.
- These compounds demonstrate stable interactions with CLIC1, validated through MD simulations.
- The identified structural scaffolds can serve as a basis for designing novel CLIC1-targeting anti-cancer drugs.
