Discovery of potent inhibitor for matrix metalloproteinase-9 by pharmacophore based modeling and dynamics simulation studies.
Matrix metalloproteinase-9 (MMP-9) is an attractive target for anticancer therapy. In the present study ligand based pharmacophore modeling was performed to elucidate the structural elements for a diverse class of MMP-9 inhibitors. The pharmacophore model was validated through Güner-Henry (GH) scoring method. The final pharmacophore model consisted of three hydrogen bond acceptors (HBA), and two ring aromatic regions (RA). This model was utilized to screen the natural compound database to seek novel compounds as MMP-9 inhibitors. The identified hits were validated using molecular docking and molecular dynamics simulation studies. Finally, one compound named Hinokiflavone from Juniperus communis had high binding free energy of -26.54kJ/mol compared with the known inhibitors of MMP-9. Cytotoxicity for hinokiflavone was evaluated by MTT assay. Inhibition of MMP-9 in the presence of hinokiflavone was detected by gelatin zymography and gelatinolytic inhibition assay. Results revealed that the natural compounds derived based on the developed pharmacophore model would be useful for further design and development of MMP-9 inhibitors.
Department of Bioinformatics, SRM University, Kattankulathur, Kancheepuram District 603 203, India.
Sukesh
S
Kalva
Chemical Laboratory, Central Leather Research Institute, Council of Scientific and Industrial Research, Adyar, Chennai 600 020, India.
E R
ER
Azhagiya Singam
Chemical Laboratory, Central Leather Research Institute, Council of Scientific and Industrial Research, Adyar, Chennai 600 020, India.
V
V
Rajapandian
Department of Bioinformatics, SRM University, Kattankulathur, Kancheepuram District 603 203, India. Electronic address: saleena.m@ktr.srmuniv.ac.in.
Lilly M
LM
Saleena
Chemical Laboratory, Central Leather Research Institute, Council of Scientific and Industrial Research, Adyar, Chennai 600 020, India. Electronic address: subuchem@hotmail.com.
V
V
Subramanian
D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D020780:Matrix Metalloproteinase 9 / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D017433:Protein Structure, Secondary; D021281:Quantitative Structure-Activity Relationship; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D020780:Matrix Metalloproteinase 9
Docking; Gelatin zymography; MTT; Molecular dynamics simulation; Pharmacophore modeling