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

Zhu R, Liu Q, Tang J, Li H, Cao Z - Int J Mol Sci (2011)

Bottom Line: 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 Article: PubMed Central - PubMed

Affiliation: Department of Bioinformatics, School of Life Sciences and Technology, Tongji University, 1239 Siping Road, Shanghai 200092, China; E-Mails: rxzhu@tongji.edu.cn (R.Z.); qiliu@tongji.edu.cn (Q.L.).

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.

Show MeSH

Related in: MedlinePlus

SAReport of Hedgehog inhibitors.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
getmorefigures.php?uid=PMC3116172&req=5

f3-ijms-12-03018: SAReport of Hedgehog inhibitors.

Mentions: The first important finding is that through such SAReport we validated our former finding that only the data to cell line NCI-H446 can obtain a reasonable QSAR modeling result (indicated in Figure 3). Secondly, our SAReport has shown that demethylation, methylation and hydroxylation at a specific position of the inhibitor scaffold may highly improve their activity. As indicated in Figure 3, demethylation at position 8, methylation at position 7 and hydroxylation at position 11 provided three possible ways to improve the inhibitor’s activity. In addition, the SAReport shows that demethylation seems to be the most efficient approach to improve activity among others. This conclusion provides the first proven set of efficient inhibitor structure modification methods in order to improve their activities. All these results will definitely shed new light on the future work of inhibitor synthesis.


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

Zhu R, Liu Q, Tang J, Li H, Cao Z - Int J Mol Sci (2011)

SAReport of Hedgehog inhibitors.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3116172&req=5

f3-ijms-12-03018: SAReport of Hedgehog inhibitors.
Mentions: The first important finding is that through such SAReport we validated our former finding that only the data to cell line NCI-H446 can obtain a reasonable QSAR modeling result (indicated in Figure 3). Secondly, our SAReport has shown that demethylation, methylation and hydroxylation at a specific position of the inhibitor scaffold may highly improve their activity. As indicated in Figure 3, demethylation at position 8, methylation at position 7 and hydroxylation at position 11 provided three possible ways to improve the inhibitor’s activity. In addition, the SAReport shows that demethylation seems to be the most efficient approach to improve activity among others. This conclusion provides the first proven set of efficient inhibitor structure modification methods in order to improve their activities. All these results will definitely shed new light on the future work of inhibitor synthesis.

Bottom Line: 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 Article: PubMed Central - PubMed

Affiliation: Department of Bioinformatics, School of Life Sciences and Technology, Tongji University, 1239 Siping Road, Shanghai 200092, China; E-Mails: rxzhu@tongji.edu.cn (R.Z.); qiliu@tongji.edu.cn (Q.L.).

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.

Show MeSH
Related in: MedlinePlus