Mulberroside A could serve as a pan inhibitor for the tyrosine kinase domains of the HER family

Abstract

Numerous medicines were authorized for their targeting of the tyrosine kinase domain (TKD) of human epidermal receptors (HER). However, it has been demonstrated that these TKDs exhibit persistent resistance, necessitating the development of additional inhibitors with different modes of action. A single pharmacophore can be manipulated to create a pan-inhibitor where the binding site of these receptors has been highly conserved. The development of anti-cancer agents and the introduction of synergistic action to increase the efficacy of current medications have both recently benefited from the use of medicinal plants and herbal extracts as a reliable source. The binding affinity to the TKDs was predicted by molecular docking, followed by molecular dynamic simulation to examine the changes in the motion of the enzymes, with a focus on the components responsible for catalytic activity (C α-helix), activation (activation loop), and autophosphorylation (C-terminal loop). According to the ∆G value provided by Autodock Vina (-40.54, -40.12, -37.20, -37.62 kJ/mol for HER1, HER2, HER3, and HER4, respectively) and MM/PBSA, which indicates a strong affinity for the TKDs, the outcomes are undeniably positive. Root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration (Rg), solvent accessible surface area (SASA), and the principal component analysis (PCA) detected significant dynamic changes in the TKDs, particularly in the C α-helix and the activation loop for all TKDs, suggesting that mulberroside A may alter the function of these enzymes. This study will expand our understanding of the dynamics of the TKDs and shed light on the anticancer potential of the polyphenolic compounds.