Kumar, Kodidasu Satish Velayutham, Ravichandiran Roy, Kuldeep K. 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 <p>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</p><p>two-dimensional</p>3D<p>three-dimensional</p>FDA<p>Food and Drug Administration</p>MM-GBSA<p>Molecular Mechanics Generalized Born Surface Area</p>MMPs<p>matrix metalloproteinases</p>MMP-13<p>matrix metalloproteinase 13</p>NMR<p>nuclear magnetic resonance</p>OA<p>osteoarthritis</p>PDB<p>Protein Data Bank</p>PDB-ID<p>Protein Data Bank ID</p>PLIP<p>protein–ligand interaction profiler</p>ROC<p>receiver operating characteristic,</p>RMSD<p>root mean square deviation</p> <p></p> <p>two-dimensional</p> <p>three-dimensional</p> <p>Food and Drug Administration</p> <p>Molecular Mechanics Generalized Born Surface Area</p> <p>matrix metalloproteinases</p> <p>matrix metalloproteinase 13</p> <p>nuclear magnetic resonance</p> <p>osteoarthritis</p> <p>Protein Data Bank</p> <p>Protein Data Bank ID</p> <p>protein–ligand interaction profiler</p> <p>receiver operating characteristic,</p> <p>root mean square deviation</p> <p>Communicated by Ramaswamy H. Sarma</p> Osteoarthritis;MMP-13;docking;virtual screening;drug repurposing 2019-08-12
    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
10.6084/m9.figshare.9536948.v1