Proteochemometric modeling of the inhibition complexes of matrix metalloproteinases with N-hydroxy-2-[(phenylsulfonyl)amino]acetamide derivatives using topological autocorrelation interaction matrix and model ensemble averaging.
A target-ligand QSAR approach using autocorrelation formalism was developed for modeling the inhibitory potency (pIC(50)) toward matrix metalloproteinases (MMP-1, MMP-2, MMP-3, MMP-9, and MMP-13) of N-hydroxy-2-[(phenylsulfonyl)amino]acetamide derivatives. Target and ligand structural information was encoded in the Topological Autocorrelation Interaction matrix calculated from 2D topological representation of inhibitors and protein sequences. The relevant Topological Autocorrelation Interaction descriptors were selected by genetic algorithm-based multilinear regression analysis and Bayesian-regularized genetic neural network approaches. A model ensemble strategy was employed for achieving robust and reliable linear and non-linear predictors having nine topological autocorrelation interaction descriptors with square correlation coefficients of ensemble test-set fitting (R(2)(test)) about 0.80 and 0.87, respectively. Electrostatic and hydrophobicity/hydrophilicity properties were the most relevant on the optimum models. In addition, the distribution of the inhibition complexes on a self-organized map depicted target dependence rather than an inhibitor similarity pattern.
Fernández
Michael
M
Molecular Modeling Group, Center for Biotechnological Studies, Faculty of Agronomy, University of Matanzas, Matanzas 44740, Cuba. michael_llamosa@yahoo.com
Fernández
Leyden
L
Caballero
Julio
J
Abreu
José Ignacio
JI
Reyes
Grethel
G
D000081:Acetamides / Q000737:chemistry*; D000465:Algorithms; D004791:Enzyme Inhibitors / Q000737:chemistry; D057927:Hydrophobic and Hydrophilic Interactions; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000737:chemistry; D008958:Models, Molecular; D016571:Neural Networks, Computer; D021281:Quantitative Structure-Activity Relationship; D055672:Static Electricity
D000081:Acetamides; D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases