Predicting Novel Antitumor Agents: 3D-Pharmacophore Mapping of beta-N-biaryl Ether Sulfonamide-Based Hydroxamates as Potentially MMP-2 Inhibitors

Autor(es)

Turra, Kely Medeiros ^[1] ; Rivelli, Diogo Pineda ^[1] ; de Moraes Barros, Silvia Berlanga ^[1] ; Mesquita Pasqualoto, Kerly Fernanda ^[2]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Lab Cytopathol, Dept Clin Chem & Toxicol, Fac Pharmaceut Sci, BR-05508000 Sao Paulo - Brazil

^[2] Butantan Inst, Biochem & Biophys Lab, BR-05503900 Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: MOLECULAR INFORMATICS; v. 33, n. 9, p. 573-587, SEP 2014.
• Citações Web of Science: 2

Resumo

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 beta-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 (R-1) 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. (AU)

• Processo FAPESP: 10/19142-1 - Aplicação de Modelagem Molecular e de formalismo de CAMD (computer-Aided Molecular Design) na elucidação do mecanismo de ação de inibidores de metaloproteinases de matriz.
• Beneficiário: Kely Medeiros Turra
• Modalidade de apoio: Bolsas no Brasil - Doutorado