Molecular docking, pharmacological profiling, and MD simulations of glycolytic inhibitors targeting novel SARS CoV-2 main protease and spike protein.

Abstract

Abstract: Coronavirus infection (COVID-19), designated a global health emergency by the World Health Organization in 2020, continues to spur the search for effective therapeutics. The causative agent, SARS-CoV-2, depends on viral proteins and host metabolic reprogramming for replication. This study explores the potential of glycolytic inhibitors as dual-action agents against SARS-CoV-2, explicitly targeting the main protease and the spike protein due to their critical roles in viral replication and cellular entry. These inhibitors disrupt the activity of viral proteins and host cell glycolysis, thereby preventing viral propagation. Through a combination of virtual screening, molecular docking, and molecular dynamics simulations, fluoro-deoxy-glucose folate (FDGF) and N-(2-fluoro-3-(6-O-glucosylpropyl-azomycin)) were identified as potent candidates. The docking results showed strong binding affinities, with scores of -8.6 and -7.1 kcal/mol for main protease and -9.9 and - 7.5 kcal/mol for spike receptor-binding domain bound to ACE2. Further molecular dynamic simulations confirmed the stability of the FDGF complexes, with RMSD fluctuations consistently remained within 1.6-2.9 Å over a 100 ns trajectory. Additionally, MM-GBSA binding free energy calculations revealed favorable binding energies, underscoring the stability and potential efficacy of these compounds. Overall, the findings suggest that FDGF and N-(2-fluoro-3-(6-O-glucosylpropyl-azomycin)) show promise as SARS-CoV-2 therapeutics, warranting further in vitro and in vivo validation to confirm their antiviral potential.

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Supplementary information: The online version contains supplementary material available at 10.1007/s40203-025-00336-2.