title: Predicting Novel Antitumor Agents: 3D-Pharmacophore Mapping of β-N-biaryl Ether Sulfonamide-Based Hydroxamates as Potentially MMP-2 Inhibitors.
abstract: Matrix metalloproteinases (MMP) are a group of enzymes related to extracelular matrix remodeling. Some types of MMP are overexpressed by malignant tumors, mainly the MMP-2 subtype, and have been associated to cancer invasiveness and metastasis. A receptor-independent (RI) 4D-QSAR formalism was applied, herein, to a set of forty β-N-biaryl ether sulfonamide hydroxamates, previously reported as potent MMP-2 inhibitors, in order to map 3D-pharmacophore models and predict novel antitumor agents. The best RI 4D-QSAR model was statistically significant (N=30, r(2) =0.93, q(2) =0.88, five occupancy descriptors (GCOD), LSE=0.04, LOF=0.11, outliers=0), robust and not obtained by chance. The external predictability was 75 % (test set; N=8). A different orientation (binding mode) in the MMP-2 catalytic site was suggested regarding the most hydrophobic portion (R1 ) of the compounds' structure. Compounds were predicted and their inhibitory activity against MMP-2 was calculated by using the optimum RI 4D-QSAR model. The findings have provided interesting information to drive the designing and synthesis of novel potentially MMP-2 inhibitors against melanoma invasion.
authors.affiliation: 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.forename: Kely
authors.initials: K
authors.lastname: Medeiros Turra
authors.affiliation: 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.forename: Diogo
authors.initials: D
authors.lastname: Pineda Rivelli
authors.affiliation: 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.forename: Silvia
authors.initials: S
authors.lastname: Berlanga de Moraes Barros
authors.affiliation: Biochemistry and Biophysics Laboratory, Butantan Institute, Av Vital Brasil, 1500, São Paulo, SP 05503-900, Brazil phone/fax: 55 11 2627 9856/55 11 2627 9748. kerly.pasqualoto@butantan.gov.br, kerlypasqualoto@gmail.com.
authors.forename: Kerly
authors.initials: K
authors.lastname: Fernanda Mesquita Pasqualoto
keywords: Antitumor agents; Drug design; Melanoma; Metalloproteinase; Receptor-independent 4D-QSAR