G‑Protein-Coupled\nReceptor Surface Creates\na Favorable Pathway for Membrane Permeation of Drug Molecules

G-protein-coupled receptors (GPCRs) play a crucial role\nin modulating\nphysiological responses and serve as the main drug target. Specifically,\nsalmeterol and salbutamol, which are used for the treatment of pulmonary\ndiseases, exert their effects by activating the GPCR β2-adrenergic\nreceptor (β2AR). In our study, we employed coarse-grained molecular\ndynamics simulations with the Martini 3 force field to investigate\nthe dynamics of drug molecules in membranes in the presence and absence\nof β2AR. Our simulations reveal that, in more than 50% of the\nflip-flop events, the drug molecules use the β2AR surface to\npermeate the membrane. The pathway along the GPCR surface is significantly\nmore energetically favorable for the drug molecules, which was revealed\nby umbrella sampling simulations along spontaneous flip-flop pathways.\nFurthermore, we assessed the behavior of drugs with intracellular\ntargets, such as kinase inhibitors, whose therapeutic efficacy could\nbenefit from this observation. In summary, our results show that β2AR\nsurface interactions can significantly enhance the membrane permeation\nof drugs, emphasizing their potential for consideration in future\ndrug development strategies.