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Updated: Sep 1, 2025
Spectrophotometric Screening for Potential Inhibitors of Cytosolic Glutathione S-Transferases
Published on: October 10, 2020
Targeting Glutaminase by Natural Compounds: Structure-Based Virtual Screening and Molecular Dynamics Simulation
Shams Tabrez1,2, Torki A Zughaibi1,2, Mehboob Hoque3
1King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
Abstract:
Cancer cells change their glucose and glutamine (GLU) metabolism to obtain the energy required to continue growing. Glutaminase (GLS) plays a crucial role in promoting cell metabolism for cancer cell growth; targeting GLU metabolism by inhibiting GLS has attracted interest as a potential cancer management strategy. Herein, we employed a sequential screening of traditional Chinese medicine (TCM) database followed by drug-likeness and molecular dynamics simulations against the active site of GLS. We report 12 potent compounds after screening the TCM database against GLS, followed by a drug-likeness filter with Lipinski and Veber rule criteria. Among them, ZINC03978829 and ZINC32296657 were found to have higher binding energy (BE) values than the control compound 6-Diazo-5-Oxo-L-Norleucine, with BEs of -9.3 and -9.7 kcal/mol, respectively, compared to the BE of 6-Diazo-5-Oxo-L-Norleucine (-4.7 kcal/mol) with GLS. Molecular dynamics simulations were used to evaluate the results further, and a 100 ns MD simulation revealed that the hits form stable complexes with GLS and formed 2-5 hydrogen bond interactions. This study indicates that these hits might be employed as GLS inhibitors in the battle against cancer. However, more laboratory tests are a prerequisite to optimize them as GLS inhibitors.
Insights
Researchers identified potent traditional Chinese medicine compounds that inhibit glutaminase (GLS), a key enzyme in cancer cell metabolism. These compounds show promise as novel anti-cancer agents by targeting glucose and glutamine pathways.
Area of Science:
- Biochemistry
- Pharmacology
- Oncology
Background:
- Cancer cells exhibit altered glucose and glutamine metabolism for energy.
- Glutaminase (GLS) is vital for cancer cell growth, making it a therapeutic target.
- Inhibiting GLS offers a potential strategy for cancer management.
Purpose of the Study:
- To screen traditional Chinese medicine (TCM) compounds for glutaminase (GLS) inhibition.
- To identify novel GLS inhibitors for potential cancer therapy.
- To evaluate the drug-likeness and binding stability of identified compounds.
Main Methods:
- Sequential screening of a TCM database against the GLS active site.
- Application of drug-likeness filters (Lipinski and Veber rules).
- Molecular dynamics simulations to assess binding energy and complex stability.
Main Results:
- Identified 12 potent compounds from the TCM database inhibiting GLS.
- Two compounds, ZINC03978829 and ZINC32296657, exhibited superior binding energies (-9.3 and -9.7 kcal/mol) compared to the control.
- Molecular dynamics simulations confirmed stable complexes with GLS and hydrogen bond interactions.
Conclusions:
- The identified TCM compounds demonstrate potential as GLS inhibitors.
- These compounds may serve as a basis for developing new anti-cancer drugs targeting metabolic pathways.
- Further laboratory validation is necessary to optimize these compounds for clinical use.
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