Evaluation of the interactions between flavonoid molecules and the active site of the MRXA7 protein using molecular docking

Abstract

Background: Skin wound healing, elasticity, and protective functions are closely associated with cellular regeneration and the remodeling of the extracellular matrix (ECM). MXRA7 (Matrix Remodeling Associated Protein 7) is a protein involved in ECM regulation, tissue regeneration, and inflammatory processes, and recent studies suggest that it may play a supportive role in skin wound healing. However, systematic investigations on natural small molecules capable of modulating MXRA7 activity remain limited. Flavonoids, on the other hand, have been reported to promote wound healing and ECM regulation through their antioxidant and anti-inflammatory properties. Therefore, it is hypothesized that flavonoid compounds may act as potential modulators of MXRA7 protein activity. Aim: The aim of this study was to evaluate the binding afÏnity, binding energy, and interaction characteristics of 14 naturally occurring flavonoid compounds with the active site of the MXRA7 protein using a molecular docking approach. Materials and Methods: The molecular structures of the flavonoids were obtained from the PubChem database, and their interactions with the MXRA7 protein were investigated using molecular docking with CB-Dock2 and SwissDock software. Docking results were visualized using PyMOL and evaluated based on root mean square deviation (RMSD), binding free energy (∆G), inhibition constant (Ki), pose ranking, and cluster analysis. An RMSD value of ≤ 2.0 Å was considered indicative of a stable binding pose. Results: The RMSD values of the MXRA7–flavonoid complexes ranged from 0.081 to 0.622 Å, indicating that all compounds stably occupied the binding cavity of the protein. Fisetin (0.081 Å), naringenin (0.107 Å), and hesperetin (0.107 Å) exhibited the lowest RMSD values, suggesting highly stable binding poses. The binding free energy (∆G) values ranged from −6.0 to −7.1 kcal/mol, with protopine showing the strongest binding afÏnity (∆G=−7.1 kcal/mol). Most flavonoids formed hydrogen bonds, hydrophobic interactions, and π–π interactions with key amino acid residues of MXRA7. Cluster analysis revealed that the majority of flavonoids shared a common binding mode, while fisetin, naringenin, and hesperetin formed a distinct subcluster with more stable binding poses. Ligand efÏciency (LE) analysis indicated that chrysin, apigenin, and naringenin exhibited higher LE values, reflecting greater binding efÏciency of smaller molecules. Conclution: This study demonstrates, through molecular docking analysis, that flavonoid compounds can stably interact with the active site of the MXRA7 protein. Protopine showed the strongest binding energy, whereas fisetin, naringenin, and hesperetin exhibited superior binding pose stability. These compounds may serve as potential bioactive molecules targeting MXRA7; however, further validation through molecular dynamics simulations and experimental studies is required.