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Updated: Nov 1, 2025
Author Spotlight: Streamlining Protein Target Prediction and Validation via Molecular Docking and CETSA
Published on: February 23, 2024
Identification of plant-based hexokinase 2 inhibitors: combined molecular docking and dynamics simulation studies
Asifa Khan1, Taj Mohammad2, Anas Shamsi2
1Department of Biosciences, Jamia Millia Islamia, New Delhi, India.
Abstract:
Cancer cells ferment glucose, even under aerobic conditions, following a phenomenon known as the 'Warburg effect.' Hexokinase 2 (HK2) catalyzes the crucial step of phosphorylation of glucose for subsequent utilization in glycolysis and other pathways. HK2 has been proposed as a potential therapeutic target for anti-cancer therapy because of its enhanced expression in glucose-dependent tumors. Here, we have employed structure-based virtual screening using in-house library to identify potential phytoconstituents which could inhibit the HK2 activity. The initial hits were selected based on their binding affinity towards HK2 using the molecular docking approach. Subsequently, the filters for physicochemical properties, PAINS patterns and PASS evaluation were applied to find potential hits against HK2. Finally, we have identified epigallocatechin gallate (EGCG) and quercitrin, two natural compounds with appreciable binding affinity, efficiency and specificity towards the HK2 binding pocket. Both compounds were found to be binding preferentially to the HK2 active site and showed a decent set of drug-like properties. All-atom molecular dynamics (MD) simulations for 100 ns were carried out to see the conformational dynamics, complexes stability and interaction mechanism of HK2 with EGCG and quercitrin. MD simulation results showed that HK2 forms stable protein-ligand complexes with EGCG and quercitrin with consistency throughout the trajectory. Overall, these findings suggest that EGCG and quercitrin might be further exploited as promising scaffolds in the drug development process against HK2..Communicated by Ramaswamy H. Sarma.
Insights
Epigallocatechin gallate (EGCG) and quercitrin show promise as natural inhibitors of Hexokinase 2 (HK2), a key enzyme in cancer
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Cancer cells exhibit the Warburg effect, fermenting glucose even with oxygen present.
- Hexokinase 2 (HK2) is crucial for glucose metabolism in cancer and a potential therapeutic target.
- Enhanced HK2 expression is observed in glucose-dependent tumors, highlighting its oncogenic role.
Purpose of the Study:
- To identify natural compounds that can inhibit Hexokinase 2 (HK2) activity.
- To explore potential phytoconstituents as anti-cancer therapeutics targeting HK2.
Main Methods:
- Structure-based virtual screening of an in-house library against HK2.
- Molecular docking to assess binding affinity, followed by physicochemical property filtering, PAINS, and PASS evaluation.
- All-atom molecular dynamics (MD) simulations (100 ns) to analyze complex stability and interactions.
Main Results:
- Epigallocatechin gallate (EGCG) and quercitrin were identified as potent inhibitors of HK2.
- These compounds exhibit significant binding affinity, efficiency, and specificity for the HK2 active site.
- MD simulations confirmed stable protein-ligand complexes and elucidated interaction mechanisms.
Conclusions:
- EGCG and quercitrin demonstrate favorable drug-like properties and stable binding to HK2.
- These natural compounds represent promising scaffolds for developing novel anti-cancer drugs targeting HK2.
- Further drug development efforts can exploit EGCG and quercitrin for HK2-targeted cancer therapy.
