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Discovery of selective bioactive small molecules by targeting an RNA dynamic ensemble.

Publication ,  Journal Article
Stelzer, AC; Frank, AT; Kratz, JD; Swanson, MD; Gonzalez-Hernandez, MJ; Lee, J; Andricioaei, I; Markovitz, DM; Al-Hashimi, HM
Published in: Nat Chem Biol
June 26, 2011

Current approaches used to identify protein-binding small molecules are not suited for identifying small molecules that can bind emerging RNA drug targets. By docking small molecules onto an RNA dynamic ensemble constructed by combining NMR spectroscopy and computational molecular dynamics, we virtually screened small molecules that target the entire structure landscape of the transactivation response element (TAR) from HIV type 1 (HIV-1). We quantitatively predict binding energies for small molecules that bind different RNA conformations and report the de novo discovery of six compounds that bind TAR with high affinity and inhibit its interaction with a Tat peptide in vitro (K(i) values of 710 nM-169 μM). One compound binds HIV-1 TAR with marked selectivity and inhibits Tat-mediated activation of the HIV-1 long terminal repeat by 81% in T-cell lines and HIV replication in an HIV-1 indicator cell line (IC(50) ∼23.1 μM).

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Published In

Nat Chem Biol

DOI

EISSN

1552-4469

Publication Date

June 26, 2011

Volume

7

Issue

8

Start / End Page

553 / 559

Location

United States

Related Subject Headings

  • Virus Replication
  • RNA
  • Protein Binding
  • Netilmicin
  • Molecular Structure
  • Models, Molecular
  • HIV-1
  • Drug Discovery
  • Computational Biology
  • Biochemistry & Molecular Biology
 

Citation

APA
Chicago
ICMJE
MLA
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Stelzer, A. C., Frank, A. T., Kratz, J. D., Swanson, M. D., Gonzalez-Hernandez, M. J., Lee, J., … Al-Hashimi, H. M. (2011). Discovery of selective bioactive small molecules by targeting an RNA dynamic ensemble. Nat Chem Biol, 7(8), 553–559. https://doi.org/10.1038/nchembio.596
Stelzer, Andrew C., Aaron T. Frank, Jeremy D. Kratz, Michael D. Swanson, Marta J. Gonzalez-Hernandez, Janghyun Lee, Ioan Andricioaei, David M. Markovitz, and Hashim M. Al-Hashimi. “Discovery of selective bioactive small molecules by targeting an RNA dynamic ensemble.Nat Chem Biol 7, no. 8 (June 26, 2011): 553–59. https://doi.org/10.1038/nchembio.596.
Stelzer AC, Frank AT, Kratz JD, Swanson MD, Gonzalez-Hernandez MJ, Lee J, et al. Discovery of selective bioactive small molecules by targeting an RNA dynamic ensemble. Nat Chem Biol. 2011 Jun 26;7(8):553–9.
Stelzer, Andrew C., et al. “Discovery of selective bioactive small molecules by targeting an RNA dynamic ensemble.Nat Chem Biol, vol. 7, no. 8, June 2011, pp. 553–59. Pubmed, doi:10.1038/nchembio.596.
Stelzer AC, Frank AT, Kratz JD, Swanson MD, Gonzalez-Hernandez MJ, Lee J, Andricioaei I, Markovitz DM, Al-Hashimi HM. Discovery of selective bioactive small molecules by targeting an RNA dynamic ensemble. Nat Chem Biol. 2011 Jun 26;7(8):553–559.

Published In

Nat Chem Biol

DOI

EISSN

1552-4469

Publication Date

June 26, 2011

Volume

7

Issue

8

Start / End Page

553 / 559

Location

United States

Related Subject Headings

  • Virus Replication
  • RNA
  • Protein Binding
  • Netilmicin
  • Molecular Structure
  • Models, Molecular
  • HIV-1
  • Drug Discovery
  • Computational Biology
  • Biochemistry & Molecular Biology