Screening of Sonic Hedgehog (Shh) Inhibitors in the Hedgehog Signaling Pathway from Traditional Chinese Medicine (TCM) Database Through Structure-Based Pharmacophore Design

  • Ilmi Fadhilah Rizki
  • Mochammad Arfin Fardiansyah Nasution
  • Syafrida Siregar
  • Mega Maulina Ekawati
  • Usman Sumo Friend TambunanEmail author
Conference paper
Part of the Lecture Notes in Computer Science book series (LNCS, volume 10847)


Colorectal cancer (CRC) is the second most death-leading cancer in the world. The development of CRC is closely related to the hedgehog signaling pathway. The abnormal activation of the pathway will initiate the binding of Sonic Hedgehog (Shh) to Ptch1 that can trigger the growth of abnormal cells that cause CRC. Traditional Chinese Medicine (TCM) compounds were used to inhibit Shh through structure-based pharmacophore design. This research was started by finding the pharmacophore feature of Shh, continued with docking simulation of Shh with TCM compounds. The best three TCM compounds, which are TCM-8941, TCM-28794 and TCM-32808, give the best ligand interaction and have the lowest Gibbs free binding energy. They also have good pharmacological properties that have been analyzed by using Toxtree v2.6.13, SwissADME and admetSAR. For further research, these TCM compounds may be used as drug candidates in colorectal cancer.


Sonic hedgehog Colorectal cancer Traditional Chinese Medicine Structure-Based pharmacophore design 



This research is financially supported by the Directorate of Research and Community Engagement of Universitas Indonesia (DRPM UI) through Hibah Publikasi Internasional Terindeks Untuk Tugas Akhir Mahasiswa (PITTA) UI 2327/UN2.R3.1/HKP.05.00/2018. Herewith, the authors declare that there is no conflict of interest regarding of the manuscript.


  1. 1.
    Seow, H.F., Yip, W.K., Fifis, T.: Advances in targeted and immunobased therapies for colorectal cancer in the genomic era. Onco Targets Ther. 9, 1899–1920 (2016)CrossRefGoogle Scholar
  2. 2.
    Kolterud, Å., Grosse, A.S., Zacharias, W.J., Walton, K.D., Katherine, E., Madison, B., Waghray, M., Ferris, J.E., Hu, C., Merchant, J.L., Dlugosz, A., Kottmann, A.H., Gumucio, D.L.: Paracrine Hedgehog signaling in stomach and intestine: new roles for hedgehog in gastrointestinal patterning. Gastroenterology 137, 618–628 (2009)CrossRefGoogle Scholar
  3. 3.
    Berman, D.M., Karhadkar, S.S., Maitra, A., De Oca, R.M., Gerstenblith, M.R., Briggs, K., Parker, A.R., Shimada, Y., Eshleman, J.R., Watkins, D.N., Beachy, P.A.: Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours. Nature 425, 846–851 (2003)CrossRefGoogle Scholar
  4. 4.
    Song, J., Zhang, J., Wang, J., Wang, J., Guo, X., Dong, W.: β1 integrin mediates colorectal cancer cell proliferation and migration through regulation of the Hedgehog pathway. Tumour Biol. 36, 2013–2021 (2015)CrossRefGoogle Scholar
  5. 5.
    Li, X., Yang, G., Li, X., Zhang, Y., Yang, J., Chang, J., Sun, X., Zhou, X., Guo, Y., Xu, Y., Liu, J., Bensoussan, A.: Traditional Chinese medicine in cancer care: a review of controlled clinical studies published in Chinese. PLoS ONE 8, e60338 (2013)CrossRefGoogle Scholar
  6. 6.
    Chen, C.Y.C.: TCM Database@ Taiwan: the world’s largest traditional Chinese medicine database for drug screening in silico. PLoS ONE 6, e15939 (2011)CrossRefGoogle Scholar
  7. 7.
    Sander, T., Freyss, J., Von Korff, M., Rufener, C.: DataWarrior: An open-source program for chemistry aware data visualization and analysis. J. Chem. Inf. Model. 55, 460–473 (2015)CrossRefGoogle Scholar
  8. 8.
    Bishop, B., Aricescu, A.R., Harlos, K., O’Callaghan, C.A., Jones, E.Y., Siebold, C.: Structural insights into hedgehog ligand sequestration by the human hedgehog-interacting protein HHIP. Nat. Struct. Mol. Biol. 16, 698–703 (2009)CrossRefGoogle Scholar
  9. 9.
    Molecular Operating Environment (MOE), 09 2014 (2015)Google Scholar
  10. 10.
    Daina, A., Michielin, O., Zoete, V.: SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci. Rep. 7, 1–13 (2017)CrossRefGoogle Scholar
  11. 11.
    Cheng, F., Li, W., Zhou, Y., Shen, J., Wu, Z., Liu, G., Lee, P.W., Tang, Y.: AdmetSAR: A comprehensive source and free tool for assessment of chemical ADMET properties. J. Chem. Inf. Model. 52, 3099–3105 (2012)CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Ilmi Fadhilah Rizki
    • 1
  • Mochammad Arfin Fardiansyah Nasution
    • 1
  • Syafrida Siregar
    • 1
  • Mega Maulina Ekawati
    • 1
  • Usman Sumo Friend Tambunan
    • 1
    Email author
  1. 1.Faculty of Mathematics and Natural SciencesUniversitas IndonesiaDepokIndonesia

Personalised recommendations