Background: MMP-2 enzyme is a kind of matrix metalloproteinases that digests the denatured collagens and\ngelatins. It is highly involved in the process of tumor invasion and has been considered as a promising target for\ncancer therapy. The structural requirements of an MMP-2 inhibitor are: (1) a functional group that binds the zinc\nion, and (2) a functional group which interacts with the enzyme backbone and the side chains which undergo\neffective interactions with the enzyme subsites.\nMethods: In the present study, a QSAR model was generated to screen new inhibitors of MMP-2 based on\nLââ?¬â??hydroxy tyrosine scaffold. Descriptors generation were done by Hyperchem 8, DRAGON and Gaussian98W\nprograms. SPSS and MATLAB programs have been used for multiple linear regression (MLR) and genetic algorithm\npartial least squares (GA-PLS) analyses and for theoretical validation. Applicability domain of the model was performed\nto screen new compounds. The binding site potential of all inhibitors was verified by structure-based docking according\nto their binding energy and then the best inhibitors were selected.\nResults: The best QSAR models in MLR and GA-PLS were reported, with the square correlation coefficient for\nleave-one-out cross-validation (Q2\nLOO) larger than 0.921 and 0.900 respectively. The created MLR and GA-PLS\nmodels indicated the importance of molecular size, degree of branching, flexibility, shape, three-dimensional\ncoordination of different atoms in a molecule in inhibitory activities against MMP-2.\nThe docking study indicated that lipophilic and hydrogen bonding interactions among the inhibitors and the receptor\nare involved in a ligand-receptor interaction. The oxygen of carbonyl and sulfonyl groups is important for hydrogen bonds\nof ligand with Leu82 and Ala83. R2 and R3 substituents play a main role in hydrogen bonding interactions. R1 is sited in\nthe hydrophobic pocket. Methylene group can help a ligand to be fitted in the lipophilic pocket, so two methylene\ngroups are better than one. The Phenyl group can create a ?-? interaction with Phe86.\nConclusions: The QSAR and docking analyses demonstrated to be helpful tools in the prediction of anti-cancer activities\nand a guide to the synthesis of new metalloproteinase inhibitors based on L-tyrosine scaffold.
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