https://orcid.org/0000-0001-9623-0617
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Abstract
Osteoarthritis (OA) is the most common form of arthritis with no available disease-modifying treatments, and is a major cause of disability. Matrix metalloproteinase 13 (MMP-13) is vital for OA progression and thus, inhibition of MMP-13 is an effective strategy to treat OA. Since the past few decades, drug repurposing has gained substantial popularity worldwide as a time- and cost-effective approach to find new indications for the existing drugs. Therefore, more than 40 X-ray co-crystal structures of the human MMP-13 with bound inhibitors are investigated to gain the structural insights such as conserved direct interactions with binding site residues, namely Ala-238, Thr-245 and Thr-247. Afterwards, enrichment study using active and decoy set of ligands revealed three MMP-13 structures (PDB-IDs: 1XUC, 3WV1 and 5BPA) with optimal enrichment performance. Docking-based screening of existing drugs against the three crystal structures followed by binding free-energy calculation suggested drugs namely eltrombopag, cilostazol and domperidone as potential MMP-13 inhibitors that need further experimental validation. These insights may serve as a potential starting point of further experimental validation and structure-based drug design/repurposing of MMP-13 inhibitors for the treatment of OA.
| Abbreviations | ||
| 2D | = | two-dimensional |
| 3D | = | three-dimensional |
| FDA | = | Food and Drug Administration |
| MM-GBSA | = | Molecular Mechanics Generalized Born Surface Area |
| MMPs | = | matrix metalloproteinases |
| MMP-13 | = | matrix metalloproteinase 13 |
| NMR | = | nuclear magnetic resonance |
| OA | = | osteoarthritis |
| PDB | = | Protein Data Bank |
| PDB-ID | = | Protein Data Bank ID |
| PLIP | = | protein–ligand interaction profiler |
| ROC | = | receiver operating characteristic, |
| RMSD | = | root mean square deviation |
Communicated by Ramaswamy H. Sarma
Disclosure statement
The authors declare that they have no conflict of interest.