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Virtual screening of ABCC1 transporter nucleotidebinding domains as a therapeutic target in multidrug resistant

Kanin Rungsardthong1, Sergio Mares-Sámano, Jeffrey Penny

  • 1University of Manchester, School of Pharmacy & Pharmaceutical Sciences, Stopford Building, M13 9PT, UK.

Bioinformation
|November 13, 2012
PubMed
Abstract

Insights

This study identified potential inhibitors for ABCC1, a transporter linked to cancer multidrug resistance. Virtual screening of NCI compounds revealed several promising candidates that may block xenobiotic efflux.

Area of Science:

  • Biochemistry and Molecular Biology
  • Pharmacology
  • Computational Chemistry

Background:

  • ABCC1 (ATP-binding cassette transporter 1) actively effluxes xenobiotics from cells.
  • ABCC1 expression is clinically linked to cancer multidrug resistance.
  • Inhibiting ABCC1's ATP-dependent substrate efflux may combat drug resistance.

Purpose of the Study:

  • To identify potential ABCC1 inhibitors through virtual screening of National Cancer Institute (NCI) compounds.
  • To explore compounds that can inhibit ATP binding and hydrolysis at ABCC1's nucleotide-binding domains (NBDs).

Main Methods:

  • Generated a 3D model of ABCC1 NBD2 using MODELLER and retrieved the X-ray crystal structure of ABCC1 NBD1 from the Protein Data Bank (PDB).
  • Created a pharmacophore hypothesis based on known NBD-binding flavonoids using PHASE for screening the NCI database.
  • Performed molecular docking studies using GLIDE for identified hit compounds.

Main Results:

  • Approximately 5% of hit compounds showed lower docking scores than ATP in ABCC1 NBD1, and 7% in ABCC1 NBD2.
  • Key interactions involved P-loop residues and aromatic amino acids Trp653 (NBD1) and Tyr1302 (NBD2).
  • Identified specific NCI compound IDs (e.g., NSC93033, NSC91789) as potential ABCC1 inhibitors.

Conclusions:

  • Several NCI compounds were identified as potential ABCC1 inhibitors based on docking scores and binding orientations.
  • These compounds may interfere with ABCC1's ATP-dependent function, offering a strategy against multidrug resistance.
  • Further pharmacological analysis is required to validate these potential inhibitors.
Keywords:
ABCC1DockingFlavonoidHomologyNucleotide-binding domainPharmacophore

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