Inhibitors of multidrug resistance (MDR) have affinity for MDR substrates

Area of Science:

• Biochemistry
• Molecular Biology
• Pharmacology

Background:

• Multidrug-resistance (MDR) is a significant challenge in treating bacterial infections and cancers.
• MDR is mediated by membrane proteins that actively export drugs from cells.
• This efflux reduces intracellular drug concentrations below therapeutic levels.

Purpose of the Study:

• To investigate the molecular mechanisms by which MDR inhibitors interact with MDR transporters.
• To explore the potential of MDR inhibitors to overcome drug efflux.

Main Methods:

• Molecular modeling was employed to simulate the interactions between MDR inhibitors and transporter substrates.
• Analysis focused on the binding affinity of inhibitors to MDR transporter proteins.

Main Results:

• Inhibitors of MDR were found to have significant affinity for the substrates of MDR transporters.
• This affinity suggests a mechanism where inhibitors can facilitate drug entry into cells.
• Formation of a large inhibitor-drug complex was predicted to be a poor substrate for MDR efflux pumps.

Conclusions:

• MDR inhibitors may enhance drug efficacy by facilitating cellular entry.
• The formation of inhibitor-drug complexes can 'cloak' drugs, preventing their efflux and increasing intracellular concentrations.
• This strategy offers a potential new approach to combatting multidrug resistance.