Suppressing Liver Cancer via the VEGFR1 Receptor using De novo Ellagic Acid Derivatives and Co-drugs: Comprehensive In silico Biochemistry Research with ADMET, RMSD, Molecular Docking, and Molecular Dynamics Simulations.

INTRODUCTION

Ellagic acid, Formononetin, and Glycitein are bioactive polyphenols possessing anticancer activity via apoptosis, cell cycle inhibition, and oncogenic signaling pathway modulation. In particular, Ellagic acid demonstrated interesting activity towards hepatocellular carcinoma (HCC), with the potential antiangiogenic target being VEGFR1. This study explores fluorinated Ellagic acid derivatives as potential VEGFR1 inhibitors, overcoming disadvantages of Formononetin/Glycitein co-drugs, namely poor ADME properties, hERG liability, and low bioavailability.

METHODS

Geometry optimization was carried out using DFT with the B3LYP/6-31G(d,p) basis set. Molecular docking with AutoDock Vina was applied in order to assess binding energies and inhibitory constants. Further MD simulation was conducted under physiological conditions using the OPLS 3.0 force field.

RESULTS

Ellagic acid established stable hydrogen-bond interactions with VEGFR1. Fluorination improved predicted binding affinity, inhibitory potency, and lipophilicity. Although the co-drugs exhibited stronger binding energies, they showed less favorable predicted ADMET profiles and increased toxicity alerts. All complexes remained highly stable during MD simulations (RMSD <1 Å).

DISCUSSION: Prioritization of fluorinated Ellagic acid was conducted according to favorable MM/GBSA binding energy, inhibitory constant, lipophilicity, oral bioavailability, and lack of predicted hERG-related cardiotoxicity. Formononetin and Glycitein demonstrated lower drug-likeness and predicted oral bioavailability and had cardiotoxicity issues.

CONCLUSION

Fluorinated Ellagic acid derivatives could be considered as potential inhibitors of VEGFR1 due to their favorable binding characteristics and structural stability, along with predicted good ADMET properties without QikProp toxicity alerts.