Molecular Modelling of Berberine Derivatives as Inhibitors of Human Smoothened Receptor and Hedgehog Signalling Pathway Using a Newly Developed Algorithm on Anti-Cancer Drugs

Title:Molecular Modelling of Berberine Derivatives as Inhibitors of Human Smoothened Receptor and Hedgehog Signalling Pathway Using a Newly Developed Algorithm on Anti-Cancer Drugs

Volume: 12 Issue: 4

Author(s): Parham Jabbarzadeh Kaboli, Mohammad Bazrafkan, Patimah Ismail*King-Hwa Ling

Affiliation:

• Department of Biomedical Science, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang 43400, Selangor,Malaysia

Keywords: Berberine, cancer, cyclopamine, hedgehog signalling pathway, molecular dynamics simulations, molecular modeling, smoothened receptor.

Abstract: 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.

Cite this article as:

Kaboli Jabbarzadeh Parham , Bazrafkan Mohammad , Ismail Patimah *, Ling King-Hwa , Molecular Modelling of Berberine Derivatives as Inhibitors of Human Smoothened Receptor and Hedgehog Signalling Pathway Using a Newly Developed Algorithm on Anti-Cancer Drugs, Recent Patents on Anti-Cancer Drug Discovery 2017; 12 (4) . https://dx.doi.org/10.2174/1574892812666170929131247