Fig. 1

Schematic of computational kinetic model. The primary mechanism for drugs to enter the cell is via passive transport (left panel). Association of both paclitaxel and TKIs with the substrate-binding domain (SBD) occurs within the plasma membrane. Tyrosine kinase inhibitors (TKIs) interact with the nucleotide-binding domain (NBD) in the cytoplasm. Transitions between the nine distinct states of P-gp are governed by four dissociation constants (right panel): K_dP for paclitaxel binding to the SBD, K_dN for TKI binding to the SBD (“N” denotes nilotinib), K_dA for the binding of ATP to the NBD, and K_dI for TKI binding to the NBD (“I” denotes inhibitor). The values of these dissociation constants were derived from the affinities from the docking simulations and experimental data. Only the ATP-bound states lead to efflux of paclitaxel and TKIs