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.