Model of P-Glycoprotein Ligand Binding and Validation with Efflux Substrate Matched Pairs

The blood–brain barrier (BBB) poses a significant obstacle in developing therapeutics for neurodegenerative diseases and central nervous system (CNS) disorders. P-glycoprotein (P-gp), a multidrug resistance protein, is a critical gatekeeper in the BBB and plays a role in cancer chemoresistance. This paper uses cryo-EM P-gp structures as starting points with an induced fit docking (IFD) model to evaluate 19 pairs of compounds with known P-gp efflux data. The study reveals significant differences in binding energy and sheds light on structural modifications' impact on efflux properties. In the cases examined, fluorine incorporation influences the efflux by altering the molecular conformation rather than proximal heteroatom basicity. Although there are limitations in addressing covalent interactions or when binding extends into the more flexible vestibule region of the protein, the results provide valuable insights and potential strategies to overcome P-gp efflux, contributing to the advancement of drug development for both CNS disorders and cancer therapies.