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

• Published in: Molecular informatics 2014-09, Vol.33 (9), p.573-587
• Main Authors: Medeiros Turra, Kely, Pineda Rivelli, Diogo, Berlanga de Moraes Barros, Silvia, Fernanda Mesquita Pasqualoto, Kerly
• Format: Article
• Language: English
• Subjects: Antitumor agents; Drug design; Melanoma; Metalloproteinase; Receptor-independent 4D-QSAR
• ISSN: 1868-1743; 1868-1751
• DOI: 10.1002/minf.201400073

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, r2=0.93, q2=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.