Pyrazole Substituted 9-Anilinoacridines as HER2 Inhibitors Targeting Breast Cancer - An In-Silico Approach.

Background Breast cancer is one of the malignant tumours which mainly affect the female population. Total 20% of the cases of breast cancer are due to overexpression of Human epidermal growth factor receptor-2 (HER2), which is the dominant tyrosine kinase receptor. In general, 9-anilinoacridine derivatives play an important role as antitumor agents due to their DNA-intercalating properties. Objective Some novel 9-anilinoacridines substituted with pyrazole moiety(1a-z) were designed, and their HER2enzyme (PDB id-3PP0) inhibition activity was evaluated by molecular docking studies using the Glide module of Schrodinger suite 2019-4. Methods Glide module of the Schrodinger suite was used to perform docking studies, qikprop module was used for in-silico ADMET screening, and the Prime-MM-GBSA module was used for free binding energy calculations. Using GLIDE scoring functions, we can determine the binding affinity of ligands (1a-z) towards HER2. Results The inhibitory activity of ligands against HER2 was mainly due to the strong hydrophobic and hydrogen bonding interactions. Almost all the compounds 1a-z have a good binding affinity with Glide scores in the range of -4.9 to -9.75 compared to the standard drugs CK0403(-4.105) and Tamoxifen (-3.78). From the results of in-silico ADMET properties, most of the compounds fall within the recommended values. MM-GBSA binding calculations of the most potent inhibitors are more favourable. Conclusion The results of in-silico studies provide strong evidence for the consideration of valuable ligands in pyrazole substituted 9-anilinoacridines as potential HER2 inhibitors, and the compounds, 1v,s,r,d, a,o with significant Glide scores may produce significant anti-breast cancer activity for further development.