Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 1 de 1
Filter
Add more filters










Database
Language
Publication year range
1.
J Biomol Struct Dyn ; 38(10): 3074-3086, 2020 Jul.
Article in English | MEDLINE | ID: mdl-31378153

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. Abbreviations2Dtwo-dimensional3Dthree-dimensionalFDAFood and Drug AdministrationMM-GBSAMolecular Mechanics Generalized Born Surface AreaMMPsmatrix metalloproteinasesMMP-13matrix metalloproteinase 13NMRnuclear magnetic resonanceOAosteoarthritisPDBProtein Data BankPDB-IDProtein Data Bank IDPLIPprotein-ligand interaction profilerROCreceiver operating characteristic,RMSDroot mean square deviationCommunicated by Ramaswamy H. Sarma.


Subject(s)
Matrix Metalloproteinase Inhibitors , Osteoarthritis , Humans , Matrix Metalloproteinase 13 , Matrix Metalloproteinase Inhibitors/pharmacology , Molecular Docking Simulation , Osteoarthritis/drug therapy , Prospective Studies
SELECTION OF CITATIONS
SEARCH DETAIL
...