Computational Repurposing of FDA-Approved Drugs as Candidate MMP2 Inhibitors with Putative MMP3 Cross-Activity

Zekri, Saad; Ait Lahcen, Nouhaila; Liman, Wissal; Bianchini, Francesca; Oubahmane, Mehdi; Hdoufane, Ismail; Cherqaoui, Driss

doi:10.3390/ijms27177756

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Computational Repurposing of FDA-Approved Drugs as Candidate MMP2 Inhibitors with Putative MMP3 Cross-Activity

by

Saad Zekri

¹,

Nouhaila Ait Lahcen

¹

,

Wissal Liman

¹,

Francesca Bianchini

²

,

Mehdi Oubahmane

^3,*

,

Ismail Hdoufane

^1,*

and

Driss Cherqaoui

¹

Laboratory of Molecular Chemistry, Faculty of Sciences Semlalia, Cadi Ayyad University, UCA, B.P. 2390, Marrakech 40000, Morocco

²

Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, Section of Experimental Pathology and Oncology, University of Florence, 50141 Florence, Italy

³

Mohammed VI Polytechnic University (UM6P), Hay Moulay Rachid, Ben Guerir 43150, Morocco

^*

Authors to whom correspondence should be addressed.

Int. J. Mol. Sci. 2026, 27(17), 7756; https://doi.org/10.3390/ijms27177756 (registering DOI)

Submission received: 27 July 2026 / Revised: 21 August 2026 / Accepted: 27 August 2026 / Published: 29 August 2026

(This article belongs to the Special Issue Computer-Aided Drug Discovery: Insights from Computational Chemistry and Cheminformatics)

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Abstract

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.

Keywords: Idiopathic pulmonary fibrosis; Matrix metalloproteinase-2; Matrix metalloproteinase-3; Pharmacophore Modeling; molecular docking; Molecular Dynamics simulation

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MDPI and ACS Style

Zekri, S.; Ait Lahcen, N.; Liman, W.; Bianchini, F.; Oubahmane, M.; Hdoufane, I.; Cherqaoui, D. Computational Repurposing of FDA-Approved Drugs as Candidate MMP2 Inhibitors with Putative MMP3 Cross-Activity. Int. J. Mol. Sci. 2026, 27, 7756. https://doi.org/10.3390/ijms27177756

AMA Style

Zekri S, Ait Lahcen N, Liman W, Bianchini F, Oubahmane M, Hdoufane I, Cherqaoui D. Computational Repurposing of FDA-Approved Drugs as Candidate MMP2 Inhibitors with Putative MMP3 Cross-Activity. International Journal of Molecular Sciences. 2026; 27(17):7756. https://doi.org/10.3390/ijms27177756

Chicago/Turabian Style

Zekri, Saad, Nouhaila Ait Lahcen, Wissal Liman, Francesca Bianchini, Mehdi Oubahmane, Ismail Hdoufane, and Driss Cherqaoui. 2026. "Computational Repurposing of FDA-Approved Drugs as Candidate MMP2 Inhibitors with Putative MMP3 Cross-Activity" International Journal of Molecular Sciences 27, no. 17: 7756. https://doi.org/10.3390/ijms27177756

APA Style

Zekri, S., Ait Lahcen, N., Liman, W., Bianchini, F., Oubahmane, M., Hdoufane, I., & Cherqaoui, D. (2026). Computational Repurposing of FDA-Approved Drugs as Candidate MMP2 Inhibitors with Putative MMP3 Cross-Activity. International Journal of Molecular Sciences, 27(17), 7756. https://doi.org/10.3390/ijms27177756

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Computational Repurposing of FDA-Approved Drugs as Candidate MMP2 Inhibitors with Putative MMP3 Cross-Activity

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