Work

Structure-based design and molecular modelling of 9-anilinoacridine derivatives targeting estrogen receptor-α in breast cancer

Year: 2026

Type: article

Abstract: Estrogen receptor-alpha (ERα) is an important therapeutic target in hormone-dependent breast cancer due to its critical role in tumour proliferation and progression. In the present study, a series of computationally designed 9-anilinoacridine derivatives were computationally investigated as potential ERα inhibitors using an integrated in silico approach. Molecular docking studies were performed using the Glide XP module of Schrödinger Suite against the ERα crystal structure (PDB ID: 2IOG ). Among the screened derivatives, compounds II(x) and II(e) exhibited the most favourable Glide XP docking scores of −11.85 and − 11.78 kcal/mol, respectively. Binding interaction analysis revealed the involvement of hydrogen bonding, hydrophobic interactions, and π–π stacking interactions with key active-site residues of ERα. To further characterize the energetic properties of the docked complexes, MM-GBSA binding free-energy calculations were performed, where compound II(f) demonstrated the most favourable ΔG_bind value of −99.68 kcal/mol. ADMET prediction revealed variable physicochemical and drug-likeness profiles across the designed compounds, with most derivatives showing zero or one predicted Rule-of-Five violation. Furthermore, comparative 100 ns molecular dynamics simulations of the ERα complexes with II(e), II(f), II(x), and the co-crystallized ligand demonstrated relatively stable protein conformations and dynamic protein–ligand interactions, including substantial conformational and orientational rearrangement of II(f) during the simulation period. In conclusion, the present findings suggest that 9-anilinoacridine derivatives, particularly compound II(f), represent computationally prioritized candidates for further experimental investigation for the development of ERα-targeted anticancer agents against breast cancer. However, chemical synthesis and experimental validation are required to establish their ERα-binding activity, functional effects, and biological efficacy.

Source: Results in Chemistry

DOI: 10.1016/j.rechem.2026.103975