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Molecular docking approaches in identification of High affinity inhibitors of Human SMO receptor

Uday Raj Akare1, Srinivas Bandaru2, Uzma Shaheen2

  • 1Bioinformatics Research Laboratory, Eminent Biosciences, Vijaynagar, Indore - 452010, Madhya Pradesh, India.

Bioinformation
|February 12, 2015
PubMed

Insights

This study investigated hedgehog pathway inhibitors targeting the SMO receptor for cancer treatment. BMS-833923 (XL139) showed the strongest binding affinity, indicating potential as an effective cancer therapeutic.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Aberrant activation of the Hedgehog (Hh) signaling pathway is a key driver in various cancers, including prostate, lung, pancreas, breast, brain, and skin.
  • The Smoothened (SMO) receptor is a critical component of the Hh pathway, making it a significant therapeutic target.

Purpose of the Study:

  • To evaluate and compare the binding affinities of eight established Hh pathway inhibitors against the SMO receptor.
  • To identify the most effective inhibitor among the tested compounds for potential cancer therapy.

Main Methods:

  • Molecular docking simulations were employed to assess the binding affinities of eight inhibitors (Cyclopamine, Saridegib, Itraconazole, LDE-225, TAK-441, BMS-833923 (XL139), PF-04449913, and Vismodegib) to the SMO receptor.
  • The MolDock scoring algorithm was utilized for quantitative assessment of binding.
  • Pharmacophoric feature analysis was performed on the lead compound.

Main Results:

  • Exelxis® BMS-833923 (XL139) exhibited the highest binding affinity to the SMO receptor, as determined by the MolDock scoring.
  • Pharmacophoric evaluation of BMS-833923 (XL139) confirmed significant and favorable ligand-receptor interactions.

Conclusions:

  • BMS-833923 (XL139) demonstrates superior binding affinity and favorable pharmacophoric characteristics, positioning it as a promising candidate for targeting the Hh pathway in cancer treatment.
  • Further investigation into BMS-833923 (XL139) is warranted for its clinical development as an anti-cancer agent.
Keywords:
BMS 833923Hedgehog PathwaySMO InhibitorsTumorogenesis

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