Computational investigation of naturally occurring anticancer agents in regulating Hedgehog pathway proteins

Area of Science:

• Biochemistry
• Molecular Biology
• Pharmacology

Background:

• The Hedgehog signaling pathway regulates embryonic development but its aberrant activation in mature tissues is linked to tumorigenesis.
• Current therapeutic strategies lack effectiveness in inhibiting key proteins driving Hedgehog-related cancers.
• Novel inhibitors are urgently needed to block the abnormal activation of this critical pathway.

Purpose of the Study:

• To identify natural compounds that can inhibit the Hedgehog signaling pathway.
• To evaluate the binding affinities of seventeen naturally occurring antitumorigenic compounds against key Hedgehog pathway proteins.
• To assess the stability and interaction of potential inhibitors using molecular dynamics simulations.

Main Methods:

• In silico screening of seventeen natural compounds against four key regulatory proteins of the Hedgehog pathway using AutoDock v4.2.6.
• Molecular docking analysis to determine binding affinities.
• 100-nanosecond molecular dynamic simulations using Gromacs v5.1.4 to analyze protein-ligand complex stability.

Main Results:

• Liriodenine demonstrated strong binding affinities to Smoothened (-7.61 kcal/mol), Patched-I (-8.14 kcal/mol), and Gli-II (-6.15 kcal/mol).
• 2",4-dihydroxy-3-methoxy chalcone exhibited the highest binding affinity to Sonic Hedgehog protein (-7.04 kcal/mol).
• Molecular dynamics simulations confirmed stable interactions between Liriodenine and 2",4-dihydroxy-3-methoxy chalcone with their respective target proteins.

Conclusions:

• Liriodenine and 2",4-dihydroxy-3-methoxy chalcone are identified as potential novel inhibitors of the Hedgehog pathway.
• These compounds warrant further investigation through in vitro and in vivo studies for therapeutic development.
• The study highlights the potential of natural products in targeting oncogenic signaling pathways.