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Biosensor-based High Throughput Biopanning and Bioinformatics Analysis Strategy for the Global Validation of Drug-protein Interactions
Published on: December 1, 2020
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Computationally accelerated identification of P-glycoprotein inhibitors
Lauren A McCormick1,2,3, James W McCormick1,2,3, Chanyang Park1,2,3
1Department of Biological Sciences, Southern Methodist University, Dallas, Texas, United States of America.
Plos One
|August 13, 2025
Summary
Researchers identified new P-glycoprotein (P-gp) inhibitors targeting its nucleotide binding domains to combat cancer multidrug resistance (MDR). These novel compounds show promise in resensitizing cancer cells to chemotherapy without harming healthy cells.
Area of Science:
- Biochemistry
- Pharmacology
- Computational Chemistry
Background:
- P-glycoprotein (P-gp) overexpression drives multidrug resistance (MDR) in cancer, limiting chemotherapy efficacy.
- Existing P-gp inhibitors often fail due to substrate binding and pharmacokinetic issues.
- Targeting P-gp's nucleotide binding domains offers a novel strategy to overcome MDR.
Purpose of the Study:
- To develop an enhanced computational pipeline for discovering novel P-gp inhibitors.
- To identify P-gp inhibitors targeting the cytoplasmic nucleotide binding domains.
- To evaluate the efficacy and safety of newly identified P-gp inhibitors in reversing MDR.
Main Methods:
- Utilized a computationally accelerated drug discovery pipeline with iterative molecular docking.
- Employed targeted molecular dynamics simulations to generate multiple P-gp conformations.
- Screened custom Tanimoto chemical datasets to maximize ligand diversity.
- Tested identified inhibitors in P-gp overexpressing human cancer cell lines.
Main Results:
- Identified nine novel P-gp inhibitors with a 13.4% hit rate.
- Demonstrated that these inhibitors reverse MDR in two human cancer cell lines.
- All identified inhibitors were non-toxic to non-cancerous human cells.
- Six inhibitors were unlikely to be P-gp transport substrates.
Conclusions:
- The cytoplasmic nucleotide binding domains of P-gp are a viable and underappreciated target for MDR reversal.
- The developed computational pipeline effectively identifies novel P-gp inhibitors.
- The identified compounds represent promising candidates for lead optimization in cancer therapy.
