Cordycepin and Its Structural Derivatives Effectively Suppress the High Expression of Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase in Breast Carcinomas: A Computational Drug Development Approach.

Background: Breast cancer is a frequently diagnosed malignant disease and the primary cause of mortality among women with cancer worldwide. The therapy options are influenced by the molecular subtype due to the intricate nature of the condition, which consists of various subtypes. By focusing on the activation of receptors, Epidermal Growth Factor Receptor (EGFR) tyrosine kinase can be utilized as an effective drug target for therapeutic purposes of breast cancer.

Objectives: The objective of this study is to compare the underlying pharmacological properties of several modified agents to the parental Cordycepin to target and inhibit the EGFR tyrosine kinase high expression, and to discover the inhibitor with the highest affinity for this drug target to treat the breast cancer patients.

Methods: The Maestro Application of Schrödinger Suite Paid Software was initially employed for conducting extra precision (XP) structure-based virtual screening to evaluate the binding affinity of the Cordycepin and its 500 structural derivatives with the EGFR tyrosine kinase protein structure. In addition, the anti-breast cancer activity of the chosen compounds was assessed by looking at their drug-likeness and ADMET characteristics using Lipinski's rule of five along with Quantitative structure- activity relationship (QSAR) validation, the prediction of cell line anti-cancer, as well as anti- breast cancer activity of top docked scored compounds. Subsequently, the Desmond paid software- based molecular dynamics simulations (MDS) were conducted for a duration of 100 nanoseconds on the promising candidates followed by the binding free energy estimation was performed utilizing MM-GBSA analysis. To determine the stability of the protein-ligand complex, root-meansquare deviation (RMSD), root-mean-square fluctuation (RMSF), protein-ligand interactions, and other necessary parameters were evaluated from the 100 ns MDS Trajectory.

Results: Based on the overall analysis of our study, N (6)-octylamine adenosine (CID-194932) reported the optimum inhibitory potential against the EGFR tyrosine kinase protein, followed by Adenosine 5-monophosphate (CID-83862) and Cordycepin (CID-6303), which compared favorably to the control drug Vandetanib (CID-3081361).

Conclusion: Consequently, these derivative compounds Cordycepin have the potential to be utilized as lead molecules in the development of highly effective and potent EGFR tyrosine kinase inhibitors for the treatment of breast cancer patients.