title: Constructing and Validating 3D-pharmacophore Models to a Set of MMP-9 Inhibitors for Designing Novel Anti-melanoma Agents.
abstract: A receptor-independent (RI) four-dimensional structure-activity relationship (4D-QSAR) formalism was applied to a set of sixty-four β-N-biaryl ether sulfonamide hydroxamate derivatives, previously reported as potent inhibitors against matrix metalloproteinase subtype 9 (MMP-9). MMP-9 belongs to a group of enzymes related to the cleavage of several extracellular matrix components and has been associated to cancer invasiveness/metastasis. The best RI 4D-QSAR model was statistically significant (N=47; r(2) =0.91; q(2) =0.83; LSE=0.09; LOF=0.35; outliers=0). Leave-N-out (LNO) and y-randomization approaches indicated the QSAR model was robust and presented no chance correlation, respectively. Furthermore, it also had good external predictability (82 %) regarding the test set (N=17). In addition, the grid cell occupancy descriptors (GCOD) of the predicted bioactive conformation for the most potent inhibitor were successfully interpreted when docked into the MMP-9 active site. The 3D-pharmacophore findings were used to predict novel ligands and exploit the MMP-9 calculated binding affinity through molecular docking procedure.
authors: Laboratory of Cytopathology, Department of Clinical Chemistry and Toxicology, Faculty of Pharmaceutical Sciences, University of São Paulo, Av Prof Lineu Prestes 580, São Paulo, SP 05508-000, Brazil.
authors: Kely
authors: K
authors: Medeiros Turra
authors: Laboratory of Cytopathology, Department of Clinical Chemistry and Toxicology, Faculty of Pharmaceutical Sciences, University of São Paulo, Av Prof Lineu Prestes 580, São Paulo, SP 05508-000, Brazil.
authors: Diogo
authors: D
authors: Pineda Rivelli
authors: Laboratory of Cytopathology, Department of Clinical Chemistry and Toxicology, Faculty of Pharmaceutical Sciences, University of São Paulo, Av Prof Lineu Prestes 580, São Paulo, SP 05508-000, Brazil.
authors: Silvia
authors: S
authors: Berlanga de Moraes Barros
authors: Biochemistry and Biophysics Laboratory, Butantan Institute, Av Vital Brasil, 1500, São Paulo, SP 05503-900, Brazil. kerlypasqualoto@gmail.com.
authors: Kerly Fernanda
authors: KF
authors: Mesquita Pasqualoto
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry*; D020134:Catalytic Domain; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D006877:Hydroxamic Acids / Q000737:chemistry; D020780:Matrix Metalloproteinase 9 / Q000737:chemistry*; D061965:Matrix Metalloproteinase Inhibitors / Q000737:chemistry*; D008545:Melanoma / Q000188:drug therapy* / Q000201:enzymology; D062105:Molecular Docking Simulation; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D013449:Sulfonamides / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; D013449:Sulfonamides; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9
keywords: 4D-QSAR; MMP-9; computer-aided drug design; melanoma; molecular docking