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

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

Keywords:

• Osteoarthritis
• MMP-13
• docking
• virtual screening
• drug repurposing

Disclosure statement

The authors declare that they have no conflict of interest.