A study on quantitative structure-activity relationship and molecular docking of metalloproteinase inhibitors based on L-tyrosine scaffold.
BACKGROUND
MMP-2 enzyme is a kind of matrix metalloproteinases that digests the denatured collagens and gelatins. It is highly involved in the process of tumor invasion and has been considered as a promising target for cancer therapy. The structural requirements of an MMP-2 inhibitor are: (1) a functional group that binds the zinc ion, and (2) a functional group which interacts with the enzyme backbone and the side chains which undergo effective interactions with the enzyme subsites.


METHODS
In the present study, a QSAR model was generated to screen new inhibitors of MMP-2 based on L-hydroxy tyrosine scaffold. Descriptors generation were done by Hyperchem 8, DRAGON and Gaussian98W programs. SPSS and MATLAB programs have been used for multiple linear regression (MLR) and genetic algorithm partial least squares (GA-PLS) analyses and for theoretical validation. Applicability domain of the model was performed to screen new compounds. The binding site potential of all inhibitors was verified by structure-based docking according to their binding energy and then the best inhibitors were selected.


RESULTS
The best QSAR models in MLR and GA-PLS were reported, with the square correlation coefficient for leave-one-out cross-validation (Q(2) LOO) larger than 0.921 and 0.900 respectively. The created MLR and GA-PLS models indicated the importance of molecular size, degree of branching, flexibility, shape, three-dimensional coordination of different atoms in a molecule in inhibitory activities against MMP-2. The docking study indicated that lipophilic and hydrogen bonding interactions among the inhibitors and the receptor are involved in a ligand-receptor interaction. The oxygen of carbonyl and sulfonyl groups is important for hydrogen bonds of ligand with Leu82 and Ala83. R2 and R3 substituents play a main role in hydrogen bonding interactions. R1 is sited in the hydrophobic pocket. Methylene group can help a ligand to be fitted in the lipophilic pocket, so two methylene groups are better than one. The Phenyl group can create a π-π interaction with Phe86.


CONCLUSIONS
The QSAR and docking analyses demonstrated to be helpful tools in the prediction of anti-cancer activities and a guide to the synthesis of new metalloproteinase inhibitors based on L-tyrosine scaffold.
Department of Medicinal Chemistry, Faculty of Pharmacy, Pharmaceutical Science Research Center, Tehran University of Medical Science, Tehran, Iran. mabbasi@pharm.mui.ac.ir.|Department of Medicinal Chemistry, Faculty of Pharmacy, Isfahan University of Medical Sciences, 81746-73461, Isfahan, Iran. mabbasi@pharm.mui.ac.ir.
Maryam
M
Abbasi
Department of Medicinal Chemistry, Faculty of Pharmacy, Pharmaceutical Science Research Center, Tehran University of Medical Science, Tehran, Iran. fr_750@yahoo.com.
Fatemeh
F
Ramezani
Medicinal & Natural Product Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran. mm_elyasi@yahoo.com.
Maryam
M
Elyasi
Department of Medicinal Chemistry, Faculty of Pharmacy, Isfahan University of Medical Sciences, 81746-73461, Isfahan, Iran. sadeghi@pharm.mui.ac.ir.
Hojjat
H
Sadeghi-Aliabadi
Department of Medicinal Chemistry, Faculty of Pharmacy, Pharmaceutical Science Research Center, Tehran University of Medical Science, Tehran, Iran. amanlou@tums.ac.ir.
Massoud
M
Amanlou
D000465:Algorithms; D020134:Catalytic Domain; D015195:Drug Design; D006860:Hydrogen Bonding; D016014:Linear Models; D020778:Matrix Metalloproteinase 2 / Q000737:chemistry*; D061965:Matrix Metalloproteinase Inhibitors / Q000737:chemistry*; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D021281:Quantitative Structure-Activity Relationship; D014443:Tyrosine / Q000737:chemistry*
D061965:Matrix Metalloproteinase Inhibitors; D014443:Tyrosine; D020778:Matrix Metalloproteinase 2