article · International Journal of Molecular Sciences
Idiopathic pulmonary fibrosis is a progressive lung condition marked by severe tissue remodelling and very few treatment options. Matrix metalloproteinase-2, or MMP2, plays an important role in degrading the extracellular matrix and driving tissue remodelling, making it an attractive therapeutic target. To identify potential treatments, researchers developed a ligand-based pharmacophore model centred on MMP2 to screen a library of existing, regulatory-approved drugs. This computational screening identified 83 matching candidates, which were subsequently assessed using molecular docking targeting the active site of MMP2. The top five candidates were then investigated with molecular dynamics simulations and additionally evaluated against MMP3, another enzyme implicated in pulmonary fibrosis. Out of these, the approved drugs regorafenib and capmatinib demonstrated the strongest cross-target binding profiles, pointing to their potential as candidates for drug repurposing in fibrotic lung conditions.
Idiopathic pulmonary fibrosis is a debilitating lung condition with few effective therapies. Repurposing existing, approved medications can dramatically reduce the time and cost required to discover new therapies. Identifying that established drugs could potentially inhibit key enzymes driving fibrotic tissue damage offers a promising starting point for developing better treatments for progressive lung diseases.
This work identifies regorafenib and capmatinib as potential repurposed therapies for pulmonary fibrosis, which could interest pharmaceutical developers and respiratory drug researchers. Because the findings are based entirely on computational screening, docking, and molecular dynamics simulations, the research is at an early discovery stage. Significant wet-lab experimental validation, preclinical testing, and clinical evaluation will be required before any commercial application or clinical use can be realised.
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Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease characterized by excessive extracellular matrix remodeling and limited therapeutic options. Matrix metalloproteinase-2 is involved in extracellular matrix degradation and tissue remodeling, making it a relevant target for antifibrotic drug discovery. In this study, an MMP2-focused ligand-based pharmacophore model was developed and was applied to screen a curated FDA-approved drug library, leading to the identification of 83 pharmacophore-matching compounds. These compounds were subsequently prioritized through molecular docking against the catalytic site of MMP2, and the five best candidates were further evaluated by molecular dynamics (MD) simulations. Because of the biological relevance of MMP3 in pulmonary fibrosis, these five selected compounds were also profiled against MMP3 as a secondary target. Among them, Regorafenib (S1178) and Capmatinib (S2788) showed the most favorable cross-target profiles and were further supported by MD analysis. From these findings, S1178 and S2788 were proposed as promising MMP2-prioritized compounds with potential MMP3 cross-activity, warranting further experimental validation as candidate antifibrotic MMP modulators.
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DOI: 10.3390/ijms27177756
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