Background: Protoberberine isoquinoline alkaloids are found in many plant species. They
consist of a diverse class of secondary metabolites with many pharmacologically active members, such
as different derivatives of berberine already patented. In the development of approximately 20-25% of
all cancers, altered hedgehog (Hh) signalling is involved where the smoothened (Smo) transmembrane
receptor triggers Hh signalling pathway towards Gli1 gene expression.
Objective: The current study aimed to model and verify the anti-Smo activity of berberine and its derivatives
using a novel automated script.
Method: Based on the patented inventions filed on ADMET modelling until 2016, which also predicts
ADMET parameters and binding efficiency indices for all molecules, a script was developed to run
automated molecular docking for a large number of small molecules.
Results: Berberine was found to interact with Lys395 of Smo receptor via hydrogen bonding and
cation-π interactions. In addition, π-π interactions between berberine aromatic rings and two aromatic
residues in the Smo transmembrane domain, Tyr394 and Phe484, were noted. Binding efficiency indices
using an in silico approach to plot the Smo-specific binding potency of each ligand was performed.
The mRNA level of Gli1 was studied as the outcome of Hh signalling pathway to show the effect of
berberine on hedgehog signalling.
Conclusion: This study predicted the role of berberine as an inhibitor of Smo receptor, suggesting its
effectiveness in hedgehog signalling during cancer treatment.