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Mechanism behind Polysorbates' Inhibitory Effect on P-Glycoprotein.
Laust Moesgaard1, Peter Reinholdt1, Carsten Uhd Nielsen1
1Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Odense M DK-5230, Denmark.
Molecular Pharmaceutics
|May 5, 2022
Summary
Polysorbate 20 (PS20) inhibits P-glycoprotein (P-gp) by directly binding to its drug-binding domain. This interaction, driven by PS20's hydrophobic headgroup, offers a new strategy for overcoming drug resistance.
Area of Science:
- Biochemistry
- Pharmacology
- Computational Biology
Background:
- P-glycoprotein (P-gp) is a key target for improving drug bioavailability and reversing multidrug resistance in cancer.
- Nonionic surfactants like polysorbate 20 (PS20) are known P-gp inhibitors, but their precise inhibition mechanism remains unclear.
Purpose of the Study:
- To elucidate the molecular mechanism by which polysorbate 20 (PS20) inhibits P-glycoprotein (P-gp).
Main Methods:
- Multiscale molecular dynamics simulations were employed to study the interaction between PS20 and P-gp at a molecular level.
Main Results:
- The amphiphilic headgroup of PS20 exhibits high hydrophobicity, preventing its partitioning into the aqueous phase.
- This hydrophobicity drives PS20 to bind to the amphiphilic drug-binding domain (DBD) of P-gp, leading to protein inhibition.
Conclusions:
- PS20 inhibits P-gp primarily through direct binding to the drug-binding domain from the extracellular side.
- Understanding this mechanism provides insights into using surfactants as P-gp modulators.
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