Potent inhibitors precise to S1' loop of MMP-13, a crucial target for osteoarthritis.
Matrix metalloproteinase-13 (MMP-13) is the primary MMP involved in cartilage degradation through its particular ability to cleave type-II collagen. This protein is expressed by chondrocytes and synovial cells in human osteoarthritis and rheumatoid arthritis; hence, it is an attractive target for the treatment of arthritic diseases. Currently available inhibitors lack specificity for metalloproteinase because of a common Zn binding site in MMPs; thus, there is a need to identify selective MMP-13 inhibitors for osteoarthritis therapy. Because selectivity is the major concern, both ligand-based and protein-based pharmacophore methodologies were used to identity potent and selective MMP-13 inhibitors. Different hypotheses were validated, and the best hypothesis was used to screen Zinc (natural and chemical) databases to seek novel scaffolds as MMP-13 inhibitors. The identified hits were validated using different strategies, such as Glide Standard precision, extra precision, E-model energies and receiver operating curve (ROC). In addition, potent inhibitors were selected based on two criteria: a similar binding mode as that of the active site PB3 crystal ligand and crucial amino acid interactions that are catalytically important for the function of MMP-13. The candidate potent inhibitors ZINC 02535232, ZINC 08399795, ZINC 12419118 and ZINC 00624580 nearly reproduced the H-bond interactions formed in the crystal structure of 1XUC with reasonable RMSD values exhibiting a novel interaction pattern that was not previously observed in MMP-13 inhibitors. The identified potent hits with diverse chemical scaffolds may be useful in designing new MMP-13 inhibitors.
Department of Bioinformatics, SRM University, SRM Nagar, Kattankulathur, Kancheepuram District, Chennai 603203, India.
Sukesh
S
Kalva
K
K
Saranyah
P Rathi
PR
Suganya
M
M
Nisha
Lilly M
LM
Saleena
D000465:Algorithms; D016208:Databases, Factual; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D053509:Matrix Metalloproteinase 13 / Q000737:chemistry* / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D011487:Protein Conformation; D021281:Quantitative Structure-Activity Relationship; D012372:ROC Curve; D015203:Reproducibility of Results
D008024:Ligands; D061965:Matrix Metalloproteinase Inhibitors; D053509:Matrix Metalloproteinase 13
Docking; E-model energies; MMP-13; Pharmacophore; QSAR; Zinc database