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Constructing and Validating 3D‐pharmacophore Models to a Set of MMP‐9 Inhibitors for Designing Novel Anti‐melanoma Agents
Author(s) -
Medeiros Turra Kely,
Pineda Rivelli Diogo,
Berlanga de Moraes Barros Silvia,
Mesquita Pasqualoto Kerly Fernanda
Publication year - 2016
Publication title -
molecular informatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.481
H-Index - 68
eISSN - 1868-1751
pISSN - 1868-1743
DOI - 10.1002/minf.201600004
Subject(s) - pharmacophore , quantitative structure–activity relationship , chemistry , protein data bank (rcsb pdb) , matrix metalloproteinase inhibitor , stereochemistry , docking (animal) , computational biology , matrix metalloproteinase , biochemistry , biology , medicine , nursing
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.