Molecular dynamics simulation and structural characterization of (-)-carvone and cis-dihydrocarvone from Mentha piperita L. as potential MMP9 inhibitors for idiopathic pulmonary fibrosis therapy

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease involving dysregulated matrix metalloproteinase-9(MMP9) activity, leading to excessive extracellular matrix deposition and lung tissue deterioration. This study investigated bioactive compounds from Mentha piperita L. as potential MMP9 inhibitors for IPF therapy. Gas chromatography-mass spectrometry (GC–MS) analysis identified nine phytochemicals in the methanolic extract of peppermint leaves. Drug-likeness screening using Lipinski’s Rule of Five identified two lead compounds: (-)-carvone
And cis-dihydrocarvone. ADMET analysis revealed favorable pharmacokinetic properties, including appropriate solubility (-3.089 and -3.12, respectively) and blood–brain barrier permeability values (0.345 and 0.357). TOPKAT toxicity prediction classified both compounds
as non-carcinogenic with negligible skin sensitization potential. Molecular docking against MMP9 (PDB ID: 1GKD) yielded MolDock scores of -84.22 for (-)-carvone and -87.47 for cis-dihydrocarvone, indicating strong binding affinity. Molecular dynamics simulations over 100 ns demonstrated stable protein–ligand complexes with consistent RMSD values (~ 0.8 Å for ligand), sustained hydrogen bonding interactions, and minimal conformational changes. Key residues LEU188, VAL398, HIS401, and TYR423 were identified as critical for binding stability. These computational findings establish (-)-carvone and cis-dihydrocarvone as promising MMP9 inhibitor candidates for IPF treatment, warranting in vitro and in vivo experimental validation.