Molecular insights into the bioactivity of H-thiazine compounds against breast cancer cells: a computational study

Area of Science:

• Computational chemistry
• Medicinal chemistry
• Oncology

Background:

• Breast cancer remains a significant global health challenge, driving the need for innovative therapeutic strategies.
• Targeting key molecular drivers like the epidermal growth factor receptor (EGFR) is a crucial approach in developing effective breast cancer treatments.

Purpose of the Study:

• To computationally evaluate novel 4-phenyl-2H-[1,3]thiazino[3,2-a]benzimidazol-2-imine (H-thiazine) derivatives as potential inhibitors of EGFR.
• To identify promising drug candidates with improved binding affinity, pharmacokinetic properties, and stability compared to existing therapies.

Main Methods:

• Molecular docking simulations were employed to assess the binding interactions of H-thiazine derivatives with EGFR.
• ADMET profiling and molecular dynamics simulations were conducted to predict pharmacokinetic properties and assess stability.
• Binding energy calculations were performed to quantify the inhibitory potential of the compounds.

Main Results:

• Methyl- and bromine-substituted H-thiazine derivatives demonstrated superior binding affinity and stability compared to the reference drug Olmutinib.
• In silico pharmacokinetic profiling suggested favorable absorption, distribution, metabolism, and excretion properties for these derivatives.
• In silico toxicity screening revealed potential safety liabilities, including AMES mutagenicity and hERG-II inhibition.

Conclusions:

• H-thiazine derivatives represent a promising scaffold for the development of novel EGFR-targeted anti-cancer agents for breast cancer.
• While computationally validated, further experimental studies, including biochemical assays and genotoxicity testing, are essential to confirm therapeutic potential and address safety concerns.