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Investigations on inhibitors of hedgehog signal pathway: a quantitative structure-activity relationship study.

ABSTRACT: The hedgehog signal pathway is an essential agent in developmental patterning, wherein the local concentration of the Hedgehog morphogens directs cellular differentiation and expansion. Furthermore, the Hedgehog pathway has been implicated in tumor/stromal interaction and cancer stem cell. Nowadays searching novel inhibitors for Hedgehog Signal Pathway is drawing much more attention by biological, chemical and pharmological scientists. In our study, a solid computational model is proposed which incorporates various statistical analysis methods to perform a Quantitative Structure-Activity Relationship (QSAR) study on the inhibitors of Hedgehog signaling. The whole QSAR data contain 93 cyclopamine derivatives as well as their activities against four different cell lines (NCI-H446, BxPC-3, SW1990 and NCI-H157). Our extensive testing indicated that the binary classification model is a better choice for building the QSAR model of inhibitors of Hedgehog signaling compared with other statistical methods and the corresponding in silico analysis provides three possible ways to improve the activity of inhibitors by demethylation, methylation and hydroxylation at specific positions of the compound scaffold respectively. From these, demethylation is the best choice for inhibitor structure modifications. Our investigation also revealed that NCI-H466 served as the best cell line for testing the activities of inhibitors of Hedgehog signal pathway among others.

SUBMITTER: Zhu R

PROVIDER: S-EPMC3116172 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Investigations on inhibitors of hedgehog signal pathway: a quantitative structure-activity relationship study.

Zhu Ruixin R Liu Qi Q Tang Jian J Li Huiliang H Cao Zhiwei Z

International journal of molecular sciences 20110511 5

The hedgehog signal pathway is an essential agent in developmental patterning, wherein the local concentration of the Hedgehog morphogens directs cellular differentiation and expansion. Furthermore, the Hedgehog pathway has been implicated in tumor/stromal interaction and cancer stem cell. Nowadays searching novel inhibitors for Hedgehog Signal Pathway is drawing much more attention by biological, chemical and pharmological scientists. In our study, a solid computational model is proposed which ...[more]

PMID: 21686166

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Project description:BackgroundMMP-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.MethodsIn 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.ResultsThe 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.ConclusionsThe 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.

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Investigations on inhibitors of hedgehog signal pathway: a quantitative structure-activity relationship study.

Publications

Investigations on inhibitors of hedgehog signal pathway: a quantitative structure-activity relationship study.

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