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Fig. 1 | BMC Systems Biology

Fig. 1

From: A computational study of the inhibition mechanisms of P-glycoprotein mediated paclitaxel efflux by kinase inhibitors

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): KdP for paclitaxel binding to the SBD, KdN for TKI binding to the SBD (ā€œNā€ denotes nilotinib), KdA for the binding of ATP to the NBD, and KdI for TKI binding to the NBD (ā€œIā€ 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

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