GPCR surface creates a favorable pathway for membrane permeation of drug molecules

G protein-coupled receptors (GPCRs) play a crucial role in modulating physiological responses and serve as the main drug target. Specifically, salmeterol and salbutamol which are used for the treatment of pulmonary diseases, exert their effects by activating the GPCR {beta}2-adrenergic receptor ({beta}2AR). In our study, we employed coarse-grained molecular dynamics simulations with the Martini 3 force field to investigate the dynamics of drug molecules in membranes in presence and absence of {beta}2AR. Our simulations reveal that in more than 50% of the flip-flop events the drug molecules use the {beta}2AR surface to permeate the membrane. The pathway along the GPCR surface is significantly more energetically favorable for the drug molecules, which was revealed by umbrella sampling simulations along spontaneous flip-flop pathways. Furthermore, we assessed the behavior of drugs with intracellular targets, such as kinase inhibitors, whose therapeutic efficacy could benefit from this observation. In summary, our results show that {beta}2AR surface interactions can significantly enhance membrane permeation of drugs, emphasizing their potential for consideration in future drug development strategies.