Background: Because of their anti-proliferative effects, 9-anilinoacridines are important as antitumor agents with DNA-intercalating properties. In this study, anticancer drugs with 9-anilinoacridines, such as amascrine and nitracrine, were developed. Pharmacophore modelling, molecular docking, Molecular Mechanics Generalized Born Surface Area (MM-GBSA), induced fit docking and a molecular dynamics (MD) study were performed to investigate the binding affinity of 9-anilinoacridines with heterocyclic substitutes as selective human epidermal growth factor receptor 2 (HER2) inhibitors for breast carcinoma.

Methods: The pharmacophore model was developed using the Schrödinger suite 2019-2 phase module. 3D structures of dataset compounds were generated using Maestro version 9.6 and optimised using the LigPrep design of the Schrödinger suite 2019-2. To predict the binding free energy of the ligands in the complex with Protein Data Bank (pdb), we performed post-docked energy minimisation using the Prime MM-GBSA module. Induced fit docking studies were performed to determine the ligand-modulated dynamic behaviour shown in the protein MD study. Using the Desmond module in Schrödinger 2019-2, the complex in the optimized potentials for liquid simulations 3 (OPLS3) force field's explicit solvent system was investigated. Using the pharmacophore hypothesis, a statistically substantial 3 Dimensional Quantitative Structure Activity Relationship (3D-QSAR) design was created.

Results: We obtained the top five hypotheses, and according to the scoring parameters, the best model was identified as the 3D-QSAR model A-Acceptor, D-Donar, R-Ring (model AADRRR)-21. From the contour map analysis, we found that the presence of a hydrogen-bond donor and electron-withdrawing and hydrophobic features are crucial for inhibiting the HER2 enzyme. The docking study showed that the ligands have significant G-score (Glide Score) values from –4.18 to –9.96 kcal/mol. A 15-ns MD simulation was also run to determine the molecular details involving the affinity of 3m in active site 3PP0.pdb. The binding free energy was determined using the Prime MM-GBSA module, and dG binding values were observed from –35.11 to –106.87 kcal/mol.

Conclusions: We designed and developed a pharmacophore hypothesis and 3D-QSAR model and then elucidated the structural features and spatial arrangement of atoms responsible for the HER2 inhibitory activity of 9-anilinoacridines. The predicted 3D-QSAR model significantly correlated with experimentally reported in vitro antitumor activity. The findings indicated that additional pharmacophore feature modifications might enhance the HER2 inhibitory activity of 9-anilinoacridines.