Potential matrix metalloproteinase 2 and 9 inhibitors identified from Ehretia species for the treatment of chronic wounds - Computational drug discovery approaches.

Matrix metalloproteinases (MMPs) serve as prognostic factors in several pathophysiological conditions, including chronic wounds. Therefore, they are considered important therapeutic targets in the intervention and treatment of these conditions. In this study, computational tools such as molecular docking and molecular dynamics simulations were used to gain insight into protein‒ligand interactions and determine the free binding energy between Ehretia species phytoconstituents and gelatinases (MMP2 and MMP9). A total of 74 phytoconstituents from Ehretia species were compiled from the literature, and 46 of these compounds were identified as potential inhibitors of at least one type of MMP. Molecular docking revealed that lithospermic acid B, rosmarinic acid, and danshensu had stronger binding affinities against the two enzymes than the reference ligands. Furthermore, (9S, 10E, 12Z, 15Z)-9-hydroxy-10,12,15-octadecatrienoic (∗-octadecatrienoic) had a higher binding energy for MMP2, whereas caffeic anhydride and caffeic acid established stronger binding energy with MMP9 than the reference ligand. These complexes also demonstrated relatively stable, favourable, and comparable conformational changes with those of unbound proteins at 500 ns. The free energy decomposition results further provide detailed insights into the contributions of active site residues and different types of interactions to the overall binding free energy. Finally, most of the hit phytoconstituents (rosmarinic acid, caffeic anhydride, caffeic acid, and danshensu) had good physicochemical, drug-likeness, and pharmacokinetic properties. Collectively, our findings showed that phytoconstituents from Ehretia species could be beneficial in the search for novel MMP inhibitors as therapeutic agents for the treatment of chronic wounds.