Identification of plant-based hexokinase 2 inhibitors: combined molecular docking and dynamics simulation studies

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

Keywords:

• Hexokinase 2
• plant-based compounds
• epigallocatechin gallate
• quercitrin
• small molecule inhibitors
• virtual screening
• molecular dynamics simulations

Acknowledgments

AK and TM are thankful to the University Grants Commission, India, for the award of Maulana Azad National Senior Research Fellowships. MIH thanks to Council of Scientific and Industrial Research, India for financial support (Project No. 27(0368)/20/EMR-II). MAI acknowledges the support provided by Department of Science and Technology, Government of India in the form of DST-INSPIRE faculty grant (DST/INSPIRE/04/2015/000556). MFA and AH acknowledge the generous support from Research Supporting Project (No. RSP-2021-122) by King Saud University, Riyadh, Kingdom of Saudi Arabia. Authors sincerely thank to the Department of Science and Technology, Government of India for the FIST support (FIST program No. SR/FST/LSII/2020/782).

Disclosure statement

The authors declare no conflict of interest.

Additional information

Funding

Indian Council of Medical Research (Grant No. ISRM/12(22)/2020).