Network pharmacology, molecular docking and molecular dynamics simulation of chalcone scaffold-based compounds targeting breast cancer receptors

Abstract

Compounds with a chalcone scaffold-based structure have demonstrated promising anticancer biological activity. However, the molecular interactions between chalcone scaffold-based compounds and breast cancer-associated proteins remain unclear. Through network pharmacology, molecular docking, and molecular dynamics (MD) simulation analyses, compounds with a chalcone scaffold-based structure were evaluated for their interaction with potential breast cancer targets. The compounds were retrieved from the ASINEX database, resulting in 575,302 compounds. A total of 342 compounds with chalcone scaffold-based structures were discovered. From the 342 compounds that was analysed, ten were chosen due to their adherence to Lipinski’s rule, having an appropriate range of lipophilicity (LOGP), and topological polar surface area (TPSA), and absence of any toxicity. Based on target intersection, 50 target genes were found and subjected to protein-protein interaction (PPI), gene ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. Four target genes were found to be involved in the breast cancer pathway. Consequently, molecular docking was utilised to analyse the molecular interactions between the compounds and four target protein receptors. Compound 211 exhibited the highest binding affinities for the epidermal growth factor receptor (EGFR), fibroblast growth factor receptor 1 (FGFR1), oestrogen receptor (ESR1), and cyclin dependent kinase 6 (CDK6) with values of −8.95 kcal/mol, −8.60 kcal/mol, −10.33 kcal/mol, and −9.90 kcal/mol, respectively. During MD simulation, compound 211 and its respective proteins were stable, compact, and had minimal flexibility. The findings provide foundations for future studies into the interaction underlying the anti-breast cancer potential of compounds with chalcone-based scaffold structures.

Communicated by Ramaswamy H. Sarma

Keywords:

• Chalcone
• breast cancer
• network pharmacology
• molecular docking
• molecular dynamics simulations

Author contributions

NZI, MK, and HA proposed and designed this study. NZI, SA, and MK contributed to writing the manuscript. All authors performed the analyses, revised, read, and approved the manuscript.

Disclosure statement

No potential conflict of interest was reported by the authors.

Acknowledgements

The first author would like to thank Universiti Sains Malaysia (USM) for the Post-Doctoral Fellow scheme and the School of Chemical Sciences, USM for the facility.

Additional information

Funding

The authors would like to thank Kementerian Pengajian Tinggi Malaysia for the Fundamental Research Grant Scheme (FRGS) with project code FRGS/1/2022/STG04/USM/02/2 which was used to finance this research work.