Molecular Dynamics Simulations of a Central Nervous System-Penetrant Drug AZD3759 with Lipid Bilayer.

AZD3759 is an epidermal growth factor receptor inhibitor with good blood–brain barrier permeability, demonstrating encouraging activity against central nervous system metastases. However, the underlying mechanism was still unclear. In this study, the interaction between AZD3759 and membrane was studied with 1,2-dimyristoyl-sn-glycero-3-phosphocholine bilayer as a model lipid. Both the cationic and neutral state of AZD3759 were considered in the simulations, and the results show that cationic AZD3759 forms more hydrogen bonds with bilayer than neutral AZD3759, and Coulombic interaction has great effects in the transmembrane process of cationic AZD3759. AZD3759 prefers to reside in the interface between the hydrophilic headgroup region and hydrophobic region of bilayer, and the chloroflurobenzene moiety plays a crucial role in the insertion of AZD3759. PMF results suggest that the hydrophobic region of DMPC bilayer is permeable by AZD3759. Understanding the transmembrane mechanism of AZD3759 at molecular level may provide useful information to the design and optimization of anti-tumor drugs with improved BBB penetration. • The penetration mechanism of AZD3759 with DMPC bilayer was studied by molecular dynamics simulations. • Neutral AZD3759 could penetrate deeper into DMPC bilayer than protonated AZD3759. • The chloroflurobenzene moiety plays a significant role in the insertion of AZD3759 into DMPC bilayer. • The electrostatic interaction is the driving force for the initial binding of AZD3759 to DMPC bilayer. • Our findings may enhance the mechanism understanding of drugs with good BBB permeability.