Inhibiting liver cancer via the VEGFR1 receptor protein using in silico biochemistry de novo drug analogues of ellagic acid: comprehensive admet, rmsd, molecular docking, and molecular dynamics simulations

Objective: Ellagic Acid, one of the well-known Pharmacognostic molecules, has been discovered to have great potential in its new derivatives to be used as drug candidates to suppress liver cancer via the VEGFR1 receptor mechanism. This study aimed to simulate (in silico biochemistry) design two novel derivatives of Ellagic Acid, a hydroxylated analogue and an Ellagic Acid–Quercetin co-drug, to improve inhibitory binding against the VEGFR1 receptor implicated in liver cancer angiogenesis. Methods: Three-dimensional ligand structures were built and optimized using density functional theory (DFT) with the B3LYP/6-31G(d,p) basis set. Molecular docking simulations were performed using AutoDock Vina 1.2.0. The most favorable poses were subjected to molecular dynamics (MD) simulations in Desmond Maestro 2024-2 under NPT conditions (310 K, 1.01 bar) with the OPLS 3.0 force field. Binding free energies were assessed using MM/GBSA calculations. Results: The pristine Ellagic Acid possesses -89.236 kJ/mol of binding energy in Molecular Dynamics, where its de novo Hydroxylated analogue and Ellagic Acid-Quercetin co-drug possess -105.319 kJ/mol, -147.214 kJ/mol, respectively. The inhibition constant values of the two new drugs are nine times higher compared to pristine Ellagic Acid, proving their efficacy with much less dosage usage in the binding of VEGFR1 receptor’s active site. Conclusion: In two analogues of Ellagic Acid, results are so much better that they prove their worth from the perspective of in silico simulation studies in terms of being used as a VEGFR1 liver cancer transmembrane receptor inhibitor. Thus, these new molecules shed light on further in vitro cell line toxicity and in vivo studies for the future.