A systematic computational analysis of human matrix metalloproteinase 13 (MMP-13) crystal structures and structure-based identification of prospective drug candidates as MMP-13 inhibitors repurposable for osteoarthritis

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. Abbreviations2D

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

two-dimensional

three-dimensional

Food and Drug Administration

Molecular Mechanics Generalized Born Surface Area

matrix metalloproteinases

matrix metalloproteinase 13

nuclear magnetic resonance

osteoarthritis

Protein Data Bank

Protein Data Bank ID

protein–ligand interaction profiler

receiver operating characteristic,

root mean square deviation

Communicated by Ramaswamy H. Sarma