Target screening and optimization of candidate compounds for breast cancer treatment using bioinformatics and computational chemistry approaches.

Objectives: This study aimed to identify critical therapeutic targets and design potent antitumor compounds for breast cancer treatment through an integrated bioinformatics and computational chemistry approach. Methods: We conducted initial screening and target intersection analysis to identify potential protein targets, highlighting the adenosine A1 receptor as a key candidate. Molecular docking and molecular dynamics (MD) simulations were performed to evaluate the binding stability between selected compounds and the human adenosine A1 receptor-Gi2 protein complex (PDB ID: 7LD3). A pharmacophore model was constructed based on binding information to guide the virtual screening of additional compounds with activity. Furthermore, we designed and synthesized a novel molecule based on this model, followed by Results: Compound 5 exhibited stable binding to the adenosine A1 receptor, as confirmed by docking and MD simulations. Pharmacophore-based screening identified compounds 6-9 with strong binding affinities. These findings guided Molecule 10, which was rationally designed and synthesized, showing potent antitumor activity against MCF-7 cells with an IC50 value of 0.032 µM, significantly outperforming the positive control 5-FU (IC50 = 0.45 µM). Conclusion: This study advances the understanding of molecular interactions in breast cancer therapy and demonstrates the potential of Molecule 10 as a highly effective therapeutic candidate. Integrating reverse drug screening, molecular modelling, and