title: Robust design of some selective matrix metalloproteinase-2 inhibitors over matrix metalloproteinase-9 through in silico/fragment-based lead identification and de novo lead modification: Syntheses and biological assays.
abstract: Broad range of selectivity possesses serious limitation for the development of matrix metalloproteinase-2 (MMP-2) inhibitors for clinical purposes. To develop potent and selective MMP-2 inhibitors, initially multiple molecular modeling techniques were adopted for robust design. Predictive and validated regression models (2D and 3D QSAR and ligand-based pharmacophore mapping studies) were utilized for estimating the potency whereas classification models (Bayesian and recursive partitioning analyses) were used for determining the selectivity of MMP-2 inhibitors over MMP-9. Bayesian model fingerprints were used to design selective lead molecule which was modified using structure-based de novo technique. A series of designed molecules were prepared and screened initially for inhibitions of MMP-2 and MMP-9, respectively, as these are designed followed by other MMPs to observe the broader selectivity. The best active MMP-2 inhibitor had IC50 value of 24nM whereas the best selective inhibitor (IC50=51nM) showed at least 4 times selectivity to MMP-2 against all tested MMPs. Active derivatives were non-cytotoxic against human lung carcinoma cell line-A549. At non-cytotoxic concentrations, these inhibitors reduced intracellular MMP-2 expression up to 78% and also exhibited satisfactory anti-migration and anti-invasive properties against A549 cells. Some of these active compounds may be used as adjuvant therapeutic agents in lung cancer after detailed study.
authors.affiliation: Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, PO Box 17020, Jadavpur University, Kolkata 700032, India.
authors.forename: Nilanjan
authors.initials: N
authors.lastname: Adhikari
authors.affiliation: Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, PO Box 17020, Jadavpur University, Kolkata 700032, India.
authors.forename: Amit K
authors.initials: AK
authors.lastname: Halder
authors.affiliation: Cancer Biology & Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, Kolkata 700032, India.
authors.forename: Sumana
authors.initials: S
authors.lastname: Mallick
authors.affiliation: Department of Chemical Technology, University of Calcutta, 92, APC Ray Road, Kolkata 700009, India.
authors.forename: Achintya
authors.initials: A
authors.lastname: Saha
authors.affiliation: Cancer Biology & Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, Kolkata 700032, India.
authors.forename: Kishna D
authors.initials: KD
authors.lastname: Saha
authors.affiliation: Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, PO Box 17020, Jadavpur University, Kolkata 700032, India. Electronic address: tjupharm@yahoo.com.
authors.forename: Tarun
authors.initials: T
authors.lastname: Jha
mesh_terms: D000072283:A549 Cells; D000465:Algorithms; D020134:Catalytic Domain; D002465:Cell Movement / Q000187:drug effects; D015195:Drug Design; D057075:Enzyme Assays; D005971:Glutamates / Q000138:chemical synthesis / Q000494:pharmacology; D005973:Glutamine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011760:Pyrrolidinones / Q000138:chemical synthesis / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D012044:Regression Analysis; D013449:Sulfonamides / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: D005971:Glutamates; D061965:Matrix Metalloproteinase Inhibitors; D011760:Pyrrolidinones; D013449:Sulfonamides; D005973:Glutamine; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9
keywords: A549 cell line; Invasion assay; Matrix metalloproteinase 2; Pharmacophore mapping; QSAR