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.
Highlights
The hedgehog signaling pathway plays a key role in the control of cell differentiation, growth, and proliferation [1]
Based on the computational framework outlined in Material and Methods, the following results or clues were obtained for the Quantitative Structure-Activity Relationship (QSAR) modeling of inhibitors of Hedgehog signal pathway
For the self-fitting of training data, we found that the models derived from physical properties are more efficient than those derived from topological indices for QSAR modeling
Summary
The hedgehog signaling pathway plays a key role in the control of cell differentiation, growth, and proliferation [1]. Hedgehog signal pathway is composed of four important components including Sonic Hedgehog, Patched, Smoothened and Gli transcription factors. Sonic Hedgehog is a secreted protein that can transduce signals between cells. Patched acts as a receptor protein to be binded by Sonic Hedgehog. Smoothened would be activated and initiate a signaling cascade that results in the activation of Gli transcription factors when Sonic Hedgehog binds with Patched. These Gli transcription factors will translocate into the nucleus where the transcription of target genes is controlled. Recent studies have found that constitutively activating the pathway can trigger cancer in adult humans, leading to basal cell carcinoma, medulloblastoma, rhabdomyosarcoma, prostate, pancreatic and breast cancers [2,3,4,5]
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