article · Molecules
Keratoconus is a serious eye disease with unclear causes and mechanisms. In search of potential treatments, thirty-two ophthalmic medications approved by the United States Food and Drug Administration were screened computationally against two zinc-dependent enzymes, MMP-2 and MMP-9. These matrix metalloproteinases represent potential targets because blocking their catalytic activity may help manage the condition. Computational docking studies indicated that atenolol and ampicillin fit effectively into the active sites of both enzymes, interacting with the catalytic zinc ion in patterns comparable to known reference inhibitors. Subsequent molecular dynamics simulations running for fifty nanoseconds, alongside binding free-energy evaluations, confirmed that these drug-enzyme interactions remained stable over time. A pharmacophore model of MMP-9 was also developed using a co-crystallised ligand to support future drug discovery efforts. These findings indicate that repurposing existing eye medications could offer a computational strategy for managing keratoconus.
Keratoconus is a sight-threatening eye condition without clearly established mechanisms or targeted pharmacological cures. Identifying existing, approved ophthalmic medicines that can inhibit key enzymes involved in tissue breakdown offers a potentially faster route to therapy. Repurposing familiar treatments like atenolol or ampicillin could significantly reduce the time, cost, and complexity of developing interventions for patients at risk of progressive vision loss.
This work identifies a drug repurposing pathway that could enable pharmaceutical developers to explore new indications for existing ophthalmic drugs in keratoconus care. The target users would be preclinical drug development teams and translational ophthalmic researchers. Because the findings are based entirely on computational docking and molecular dynamics simulations, the research is at an early theoretical stage and requires biological validation and experimental testing before any real-world use.
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Keratoconus (KC) is a serious disease that can affect people of any race or nationality, although the exact etiology and pathogenic mechanism are still unknown. In this study, thirty-two FDA-approved ophthalmic drugs were exposed to virtual screening using docking studies against both the MMP-2 and MMP-9 proteins to find the most promising inhibitors as a proposed computational mechanism to treat keratoconus. Matrix metalloproteinases (MMPs) are zinc-dependent proteases, and MMP inhibitors (MMPIs) are usually designed to interact with zinc ion in the catalytic (CAT) domain, thus interfering with enzymatic activity. In our research work, the FDA-approved ophthalmic medications will be investigated as MMPIs, to explore if they can be repurposed for KC treatment. The obtained findings of the docking study suggest that atenolol and ampicillin are able to accommodate into the active sites of MMP-2 and MMP-9. Additionally, both exhibited binding modes similar to inhibitors used as references, with an ability to bind to the zinc of the CAT. Molecular dynamic simulations and the MM-GBSA binding free-energy calculations revealed their stable binding over the course of 50 ns. An additional pharmacophoric study was carried out on MMP-9 (PDB ID: 1GKC) using the co-crystallized ligand as a reference for the future design and screening of the MMP-9 inhibitors. These promising results open the door to further biological research to confirm such theoretical results.
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DOI: 10.3390/molecules27113584
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