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Int. J. Mol. Sci. 2011, 12(5), 3018-3033;

Investigations on Inhibitors of Hedgehog Signal Pathway: A Quantitative Structure-Activity Relationship Study

2,* and 1,*
Department of Bioinformatics, School of Life Sciences and Technology, Tongji University, 1239 Siping Road, Shanghai 200092, China
Department of Natural Medicinal Chemistry, School of Pharmacy, Second Military Medical University, Shanghai 200433, China
These authors contributed equally to this work.
Authors to whom correspondence should be addressed.
Received: 14 March 2011 / Revised: 20 April 2011 / Accepted: 28 April 2011 / Published: 11 May 2011
(This article belongs to the Section Physical Chemistry, Theoretical and Computational Chemistry)
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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. View Full-Text
Keywords: QSAR; Hedgehog signal pathway; inhibitor; cyclopamine QSAR; Hedgehog signal pathway; inhibitor; cyclopamine

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Zhu, R.; Liu, Q.; Tang, J.; Li, H.; Cao, Z. Investigations on Inhibitors of Hedgehog Signal Pathway: A Quantitative Structure-Activity Relationship Study. Int. J. Mol. Sci. 2011, 12, 3018-3033.

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