Structure-based design and molecular modelling of 9-anilinoacridine derivatives targeting estrogen receptor-α in breast cancer
4 affiliations
- 1Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education& Research, Ooty 643001, The Nilgiris, Tamil Nadu, India; Corresponding author.
- 2Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education& Research, Ooty 643001, The Nilgiris, Tamil Nadu, India
- 3Department of Pharmacology, St. Johns College of Pharmaceutical Sciences and Research, Kattappana, Idukki, Kerala, 685515, India
- 4Centre for Molecular Therapeutics, Karpagam Academy of Higher Education (Deemed to be University), Coimbatore, Tamil Nadu, 641021, India; Department of Biochemistry, Karpagam Academy of Higher Education (Deemed to be University), Coimbatore, Tamil Nadu, 641021, India
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.
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BibTeX
@article{rajagopal2026structurebased,
title = {{Structure-based design and molecular modelling of 9-anilinoacridine derivatives targeting estrogen receptor-α in breast cancer}},
author = {Kalirajan Rajagopal and Krutheesh Shanmugam and Kannan Raman and V.V. Sathibabu Uddandrao and Anuj Thakran and G.M. Dhevikarunaa and P. Luseena},
journal = {Results in Chemistry},
year = {2026},
month = oct,
doi = {10.1016/j.rechem.2026.103975},
url = {https://doi.org/10.1016/j.rechem.2026.103975},
note = {CC BY},
}
RIS
TY - JOUR
TI - Structure-based design and molecular modelling of 9-anilinoacridine derivatives targeting estrogen receptor-α in breast cancer
AU - Kalirajan Rajagopal
AU - Krutheesh Shanmugam
AU - Kannan Raman
AU - V.V. Sathibabu Uddandrao
AU - Anuj Thakran
AU - G.M. Dhevikarunaa
AU - P. Luseena
PY - 2026
DA - 2026/10/30
JO - Results in Chemistry
DO - 10.1016/j.rechem.2026.103975
UR - https://doi.org/10.1016/j.rechem.2026.103975
AB - 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.
SN - 2211-7156
ER -