Integrated Systems Biology and Computational insights of Chalcone-Pyrimidine hybrids as anti-breast Cancer agents

Abstract

Heterocyclic compounds are widely recognized for their therapeutic importance in the treatment of numerous diseases. Systems biology has emerged as a powerful approach for exploring the molecular mechanisms and therapeutic potential of bioactive compounds. In the present study, a series of chalcone-derived pyrimidine derivatives were designed and investigated for their potential using integrated systems biology and computational studies. Systems biology and enrichment analyses revealed that the designed derivatives may exert promising anti-breast cancer activity via targeting the ESR1, EGFR, ERBB2 and PIK3CA targets. In addition, the physicochemical properties, pharmacokinetic behaviour and toxicity profiles of the designed compounds were assessed, indicating favourable drug-like characteristics. Drug score values ranged from 0.30 to 0.86, calculated using the OSIRIS Molecular Property Explorer, further supporting their potential as druggable candidates. Molecular docking studies performed using the Schrödinger Suite against the selected targets showed that compounds 5H, 5G,5D and 5F were found to be potent, with binding energies of -9.399 kcal/mol (5H), -3.324 kcal/mol (5C), −9.4 kcal/mol (5F) and −8.8 kcal/mol (5F) against ESR1, EGFR, ERBB2 and PIK3CA, respectively. Furthermore, density functional theory (DFT)-based graph theoretical analysis confirmed the structural stability and correlated with the biological potential of the compounds. Overall, these findings suggest that the designed chalcone-pyrimidine derivatives may be used as therapeutic candidates for the management of breast cancer. However, in vitro and in vivo studies are warranted.