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Related Experiment Video

Updated: Apr 8, 2026

Models and Methods to Evaluate Transport of Drug Delivery Systems Across Cellular Barriers

Models and Methods to Evaluate Transport of Drug Delivery Systems Across Cellular Barriers

Published on: October 17, 2013

Multiple Drug Transport Pathways through Human P-Glycoprotein.

James W McCormick¹, Pia D Vogel¹, John G Wise¹

¹Center for Drug Discovery, Design and Delivery, Center for Scientific Computing, and Department of Biological Sciences, Southern Methodist University, Dallas, Texas 75275-0376, United States.

|July 1, 2015

Summary

P-glycoprotein (P-gp) multidrug resistance can be overcome by understanding its transport mechanism. This study reveals how P-gp moves drugs like daunorubicin and verapamil through the cell membrane, offering insights for new therapies.

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Area of Science:

Biochemistry
Molecular Biology
Pharmacology

Background:

P-glycoprotein (P-gp) is a key efflux pump contributing to multidrug resistance in cancer and infectious diseases.
Overexpression of P-gp lowers intracellular drug concentrations, leading to sub-therapeutic levels and treatment failure.
Previous studies utilized in silico methods to explore P-gp's dynamic conformational transitions.

Purpose of the Study:

To investigate the transport mechanism of P-glycoprotein (P-gp) using computational simulations.
To elucidate how P-gp translocates substrates across the cell membrane.
To understand the inhibition mechanism of P-gp by tariquidar.

Main Methods:

In silico targeted molecular dynamics simulations were employed.
Docking of transport substrates (daunorubicin, verapamil) to P-gp conformations.
Simulations of P-gp cycling through conformations open to cytoplasm and extracellular space.

Main Results:

Reproducible transport of daunorubicin and verapamil by 11-12 Å through the membrane plane was observed.
Methylpyrophosphate, a non-substrate, did not exhibit this movement.
Drug binding to specific subsites influenced the transport pathway, with stochastic side-chain interactions.
Tariquidar, a P-gp inhibitor, was studied, revealing a potential inhibition mechanism.

Conclusions:

P-gp facilitates drug transport through distinct conformational cycles.
The binding site and drug interactions dictate the transport pathway and efficiency.
Tariquidar may inhibit P-gp by stabilizing an outward-open conformation.