Investigation of the effects of phenoxy chalcones on some enzyme activities by in vitro and in silico methods

The uncontrolled cell growth that alters the genetic and metabolic pathways is called cancer. This study looked at 14 different phenoxy chalcones and their ability to be used as an anti-cancer agent. More specifically their action against essential enzymes like glucose-6-phosphate dehydrogenase (G6PD), 6-phosphogluconate dehydrogenase (6PGD), lactate dehydrogenase (LDH) and elastase. The enzymes are crucial for the survival, proliferation, and redox homeostasis of tumor cells. They are also responsible for metastasis. To determine the structure-activity relationship (SAR) of these derivatives, we used a comprehensive range of techniques including in vitro enzyme inhibition studies, molecular docking and molecular dynamics (MD) simulations. The enzyme inhibition assays showed that 5c, 5a, and 5b displayed the greatest inhibition against G6PD, LDH, and elastase with IC50 values of 25.577 μM, 26.660 μM, and 1.951 μM respectively. Compound 5c is the most effective inhibitor of 6PGD with IC50 value of 101.933 μM. The ability of some compounds to inhibit an enzyme was closely related to select functional groups, particularly halogen and methoxy substituents, which improved binding to the active sites. This study helped us see how molecules are linked and how enzymes and molecules interact. New insights were gained into how everything works. Importantly, molecule 5b has the highest binding affinity to G6PD with MolDock score of −156.218 and rerank score of −106.163. In the same way, compound 5c also showed strong interactions with 6PGD, which entails hydrogen bonding and van der Waals interactions at the active site. The stability and high binding affinities of compounds 5a and 5b with LDH and elastase were supported by docking scores and interaction profiles. Strong interactions were π-π stacking, π-alkyl interactions and hydrogen bonds which stabilize the interactions and thus make them specific. Molecular dynamics simulations confirmed the stability and efficacy of the best ligands in the active site of enzymes. The simulation results demonstrated that the ligand-protein complexes remained structurally stable under physiological conditions for over 100 nanoseconds. The strong and stable binding of the compounds 5b, 5c, and 5a to G6PD, 6PGD, and LDH respectively is supported by parameters root-mean-square deviation (RMSD), the root-mean-square fluctuation (RMSF) and binding free energy calculations. The binding energies from the MD simulations also agreed with the docking results, further affirming the reliability of the computational models used. The results suggest that phenoxy chalcone derivatives can be used as multi-target inhibitors affecting diverse metabolic and signaling pathways in cancer cells. By combining experimental and computational approaches, researchers successfully obtained a comprehensive understanding of their mode of action. This facilitates the development of novel anticancer therapies which are more efficacious and have lesser toxicity. Findings suggest phenoxy chalcones may be promising candidates for further preclinical development and subsequent clinical translation.