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.

Journal of Biomolecular Structure & Dynamics
Kodidasu Satish KumarKuldeep K Roy

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/...Continue Reading

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Citations

Jun 24, 2021·Journal of Biomolecular Structure & Dynamics· Bharathi, Kuldeep K Roy

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Methods Mentioned

BETA
X-ray
profiler
nuclear magnetic resonance

Software Mentioned

ChEMBL
LigPlot
Protein Ligand Interaction Profiler ( PLIP )
AutoDockTools
AutoDock Tools
AutoDock
GridBox
OpenBabel
AutoDock Vina
[UNK] package

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