Predicting Novel Antitumor Agents: 3D-Pharmacophore Mapping of β-N-biaryl Ether Sulfonamide-Based Hydroxamates as Potentially MMP-2 Inhibitors
| Autor: | Kerly Fernanda Mesquita Pasqualoto, Diogo Pineda Rivelli, Kely Medeiros Turra, Silvia Berlanga de Moraes Barros |
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| Rok vydání: | 2014 |
| Předmět: |
chemistry.chemical_classification
Metalloproteinase Matrix remodeling Stereochemistry Melanoma Organic Chemistry Ether Matrix metalloproteinase medicine.disease Computer Science Applications Metastasis chemistry.chemical_compound Enzyme chemistry Structural Biology Drug Discovery medicine Molecular Medicine Pharmacophore |
| Zdroj: | Molecular informatics. 33(9) |
| ISSN: | 1868-1751 |
| Popis: | 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-independ- ent (RI) 4D-QSAR formalism was applied, herein, to a set of forty b-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 signifi- cant (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 in- formation to drive the designing and synthesis of novel po- tentially MMP-2 inhibitors against melanoma invasion. |
| Databáze: | OpenAIRE |
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