Pyrazole Substituted 9-Anilinoacridines as HER2 Inhibitors Targeting Breast Cancer - An in-silico approach

Abstract

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.

Accurate Characterization of Binding Kinetics and Allosteric Mechanisms for the HSP90 Chaperone Inhibitors Using AI-Augmented Integrative Biophysical Studies

“…For each conformation, the complex structures obtained by docking were subjected to the Molecular Mechanics Generalized Born Surface Area (MM-GBSA) scoring function to calculate the binding free energy (Schrödinger, 2023). MM-GBSA, a free-energy prediction method that strikes a balance between accuracy and speed, is widely used for affinity-based virtual screening and optimization of docking structures. − For each inhibitor, the conformation with the lowest binding free energy was selected. We also investigated the similarity between the structures of the 91 inhibitors and the 41 inhibitors with complex structures determined by X-ray.…”

“…MM-GBSA, a free-energy prediction method that strikes a balance between accuracy and speed, is widely used for affinity-based virtual screening and optimization of docking structures. 58 − 61 For each inhibitor, the conformation with the lowest binding free energy was selected. We also investigated the similarity between the structures of the 91 inhibitors and the 41 inhibitors with complex structures determined by X-ray.…”

An in-silico approach of assessments of human serotonin transporter inhibitory potential of various flavonoids for anti-depressants: molecular docking, MM-GBSA, molecular dynamics simulation studies

“…Properties such as molecular weight, dipole, hydrogen bond donor, hydrogen bond acceptor, log P o/w, and Lipinski's rule of ve are identi ed and mentioned in Table 1 below. According to Lipinski's rule of ve, the molecule's molecular weight should be ≤ 500, the partition coe cient should be ≤ 5, and the number of hydrogen bond donors and acceptors should be ≤ 5 and ≤ 10, respectively (Rajagopal, Kalusalingam et al 2023). All of these qualities, together with molecular exibility, are thought to be important drivers of oral bioavailability.…”