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Amiloride docking to acid-sensing ion channel-1.

Publication ,  Journal Article
Qadri, YJ; Song, Y; Fuller, CM; Benos, DJ
Published in: The Journal of biological chemistry
March 2010

Amiloride is a small molecule diuretic, which has been used to dissect sodium transport pathways in many different systems. This drug is known to interact with the epithelial sodium channel and acid-sensing ion channel proteins, as well as sodium/hydrogen antiporters and sodium/calcium exchangers. The exact structural basis for these interactions has not been elucidated as crystal structures of these proteins have been challenging to obtain, though some involved residues and domains have been mapped. This work examines the interaction of amiloride with acid-sensing ion channel-1, a protein whose structure is available using computational and experimental techniques. Using molecular docking software, amiloride and related molecules were docked to model structures of homomeric human ASIC-1 to generate potential interaction sites and predict which analogs would be more or less potent than amiloride. The predictions made were experimentally tested using whole-cell patch clamp. Drugs previously classified as NCX or NHE inhibitors are shown to also inhibit hASIC-1. Potential docking sites were re-examined against experimental data to remove spurious interaction sites. The voltage sensitivity of inhibitors was also examined. Using the aggregated data from these computational and experimental experiments, putative interaction sites for amiloride and hASIC-1 have been defined. Future work will experimentally verify these interaction sites, but at present this should allow for virtual screening of drug libraries at these putative interaction sites.

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Published In

The Journal of biological chemistry

DOI

EISSN

1083-351X

ISSN

0021-9258

Publication Date

March 2010

Volume

285

Issue

13

Start / End Page

9627 / 9635

Related Subject Headings

  • Sodium Channels
  • Sodium Channel Blockers
  • Sequence Homology, Amino Acid
  • Protein Structure, Tertiary
  • Protein Binding
  • Patch-Clamp Techniques
  • Nerve Tissue Proteins
  • Molecular Sequence Data
  • Inhibitory Concentration 50
  • Humans
 

Citation

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Qadri, Y. J., Song, Y., Fuller, C. M., & Benos, D. J. (2010). Amiloride docking to acid-sensing ion channel-1. The Journal of Biological Chemistry, 285(13), 9627–9635. https://doi.org/10.1074/jbc.m109.082735
Qadri, Yawar J., Yuhua Song, Catherine M. Fuller, and Dale J. Benos. “Amiloride docking to acid-sensing ion channel-1.The Journal of Biological Chemistry 285, no. 13 (March 2010): 9627–35. https://doi.org/10.1074/jbc.m109.082735.
Qadri YJ, Song Y, Fuller CM, Benos DJ. Amiloride docking to acid-sensing ion channel-1. The Journal of biological chemistry. 2010 Mar;285(13):9627–35.
Qadri, Yawar J., et al. “Amiloride docking to acid-sensing ion channel-1.The Journal of Biological Chemistry, vol. 285, no. 13, Mar. 2010, pp. 9627–35. Epmc, doi:10.1074/jbc.m109.082735.
Qadri YJ, Song Y, Fuller CM, Benos DJ. Amiloride docking to acid-sensing ion channel-1. The Journal of biological chemistry. 2010 Mar;285(13):9627–9635.

Published In

The Journal of biological chemistry

DOI

EISSN

1083-351X

ISSN

0021-9258

Publication Date

March 2010

Volume

285

Issue

13

Start / End Page

9627 / 9635

Related Subject Headings

  • Sodium Channels
  • Sodium Channel Blockers
  • Sequence Homology, Amino Acid
  • Protein Structure, Tertiary
  • Protein Binding
  • Patch-Clamp Techniques
  • Nerve Tissue Proteins
  • Molecular Sequence Data
  • Inhibitory Concentration 50
  • Humans