Targeting Glutaminase by Natural Compounds: Structure-Based Virtual Screening and Molecular Dynamics Simulation Approach to Suppress Cancer Progression

• Published in: Molecules (Basel, Switzerland) Vol. 27; no. 15; p. 5042
• Main Authors: Tabrez, Shams, Zughaibi, Torki A, Hoque, Mehboob, Suhail, Mohd, Khan, Mohammad Imran, Khan, Azhar U
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.08.2022; MDPI
• Subjects: Antimitotic agents; Antineoplastic agents; Bioinformatics; Biological activity; Brain cancer; Cancer; Chemical properties; Chinese medicine; Diazooxonorleucine; Dynamic structural analysis; Early Detection of Cancer; Energy metabolism; Enzyme inhibitors; Enzymes; Glucose metabolism; Glutaminase; Glutaminase - metabolism; Glutamine; Health aspects; Herbal medicine; Humans; Hydrogen bonds; Hydrolases; Inhibitors; Laboratory tests; Ligands; Medical research; Medicine, Chinese; Metabolism; Molecular Docking Simulation; Molecular dynamics; Molecular Dynamics Simulation; Molecular structure; natural compounds; Neoplasms - drug therapy; Neoplastic Processes; Norleucine; Organic compounds; Pharmaceutical research; Proteins; Simulation; Saudi Arabia; glutaminase; natural compounds; cancer; glutamine
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules27155042

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.