%0 Journal Article %A Kumar, Kodidasu Satish %A Velayutham, Ravichandiran %A Roy, Kuldeep K. %D 2019 %T 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 %U https://tandf.figshare.com/articles/journal_contribution/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/9536948 %R 10.6084/m9.figshare.9536948.v1 %2 https://tandf.figshare.com/ndownloader/files/17166311 %K Osteoarthritis %K MMP-13 %K docking %K virtual screening %K drug repurposing %X
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
3Dthree-dimensional
FDAFood and Drug Administration
MM-GBSAMolecular Mechanics Generalized Born Surface Area
MMPsmatrix metalloproteinases
MMP-13matrix metalloproteinase 13
NMRnuclear magnetic resonance
OAosteoarthritis
PDBProtein Data Bank
PDB-IDProtein Data Bank ID
PLIPprotein–ligand interaction profiler
ROCreceiver operating characteristic,
RMSDroot 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
%I Taylor & Francis