Design, synthesis and biological evaluation of small molecule inhibitors of CD4-gp120 binding based on virtual screening

Judith M. Lalonde, Mark A. Elban, Joel R. Courter, Akihiro Sugawara, Takahiro Soeta, Navid Madani, Amy M. Princiotto, Young Do Kwon, Peter D. Kwong, Arne Schön, Ernesto Freire, Joseph Sodroski, Amos B. Smith

Research output: Contribution to journalArticle

57 Citations (Scopus)

Abstract

The low-molecular-weight compound JRC-II-191 inhibits infection of HIV-1 by blocking the binding of the HIV-1 envelope glycoprotein gp120 to the CD4 receptor and is therefore an important lead in the development of a potent viral entry inhibitor. Reported here is the use of two orthogonal screening methods, gold docking and ROCS shape-based similarity searching, to identify amine-building blocks that, when conjugated to the core scaffold, yield novel analogs that maintain similar affinity for gp120. Use of this computational approach to expand SAR produced analogs of equal inhibitory activity but with diverse capacity to enhance viral infection. The novel analogs provide additional lead scaffolds for the development of HIV-1 entry inhibitors that employ protein-ligand interactions in the vestibule of gp120 Phe 43 cavity.

Original languageEnglish
Pages (from-to)91-101
Number of pages11
JournalBioorganic and Medicinal Chemistry
Volume19
Issue number1
DOIs
Publication statusPublished - 2011 Jan 1
Externally publishedYes

Keywords

  • CD4
  • Docking
  • Entry inhibitor
  • HIV
  • Shape-based similarity
  • Virtual screening
  • gp120

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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  • Cite this

    Lalonde, J. M., Elban, M. A., Courter, J. R., Sugawara, A., Soeta, T., Madani, N., Princiotto, A. M., Kwon, Y. D., Kwong, P. D., Schön, A., Freire, E., Sodroski, J., & Smith, A. B. (2011). Design, synthesis and biological evaluation of small molecule inhibitors of CD4-gp120 binding based on virtual screening. Bioorganic and Medicinal Chemistry, 19(1), 91-101. https://doi.org/10.1016/j.bmc.2010.11.049