Molecular Docking Analysis of Two Natural Compounds with the ۴KMY Protein: A Comparative Study of Folic Acid Receptor

Folate Receptor-ẞ (FR-ẞ or ۴KMY) is a high-affinity folate-binding protein that is selectively expressed on M۲-like tumor-associated macrophages (TAMS), where it plays a central role in maintaining the immunosuppressive characteristics of the tumor microenvironment. Due to its restricted expression pattern and functional importance, FR-B has attracted growing interest as a therapeutic target for both cancer treatment and immune regulation. Recent studies have highlighted that modulating FR-B-positive macrophages can shift the balance of the microenvironment toward an anti-tumor phenotype, further emphasizing the relevance of this receptor in oncology. In the present study, we employed a structure-based molecular docking approach to investigate the interaction of two bioactive natural compounds-Oroxylin A, derived from Scutellaria baicalensis, and Luteolin-۷-O-glucoside, commonly found in Lonicera japonica, Mentha species, and Plantago major-with the binding pocket of FR-ẞ. Their docking behavior was systematically compared with folic acid, the endogenous ligand and physiological substrate of FR-ß. Docking simulations were carried out using AutoDock under physiologically relevant pH conditions, applying Gasteiger/Kollman charge assignments to ensure accurate representation of electronic distributions. Both natural compounds demonstrated strong binding affinities, with interaction energies comparable to or exceeding that of folic acid, suggesting their capability to effectively engage the FR-ẞ active site. Additional analysis of hydrogen bonding patterns and hydrophobic interactions indicated that these flavonoids may stabilize within the receptor pocket through multiple complementary contacts. Such stability raises the possibility that these compounds could modulate macrophage behavior by altering FR-ẞ signaling or ligand competition. Collectively, these results underscore the potential of plant-derived flavonoids as promising structural scaffolds for the development of new immunomodulatory or anticancer agents specifically targeting FR-B.

کلیدواژه ها:

Folate Receptor-B (FR-B) ، Molecular docking ، Flavonoid ، Macrophage ، Cancer