New insights in the in vitro characterisation and molecular modelling of the P-glycoprotein inhibitory promiscuity

Abstract : The presence of several binding sites for both substrates and inhibitors is yet a poorly explored thematic concerning the assessment of the drug-drug interactions risk due to interactions of multiple drugs with the human transport protein P-glycoprotein (P-gp or MDR1, gene ABCB1). In this study we measured the inhibitory behaviour of a set of known drugs towards P-gp by using three different probe substrates (digoxin, Hoechst 33,342 and rhodamine 123). A structure-based model was built to unravel the different substrates binding sites and to rationalize the cases where drugs were not inhibiting all the substrates. A separate set of experiments was used to validate the model and confirmed its suitability to either detect the substrate-dependent P-gp inhibition and to anticipate proper substrates for in vitro experiments case by case. The modelling strategy described can be applied for either design safer drugs (P-gp as antitarget) or to target specific sub-site inhibitors towards other drugs (P-gp as target).
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Giovanni Bocci, Amélie Moreau, Philippe Vayer, Claire Denizot, Olivier Fardel, et al.. New insights in the in vitro characterisation and molecular modelling of the P-glycoprotein inhibitory promiscuity. European Journal of Pharmaceutical Sciences, Elsevier, 2018, 121 (30), pp.85-94. ⟨10.1016/j.ejps.2018.04.039⟩. ⟨hal-01795811v3⟩

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