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Structure-activity relationships in the binding of chemically derivatized cd4 to gp120 from human immunodeficiency virus

Academic Article
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Overview

authors

  • Xie, H.
  • Ng, D.
  • Savinov, S. N.
  • Dey, B.
  • Kwong, P. D.
  • Wyatt, Richard
  • Smith, A. B.
  • Hendrickson, W. A.

publication date

  • October 2007

journal

  • Journal of Medicinal Chemistry  Journal

abstract

  • The first step in HIV infection is the binding of the envelope glycoprotein gp120 to the host cell receptor CD4. An interfacial "Phe43 cavity" in gp120, adjacent to residue Phe43 of gp120-bound CD4, has been suggested as a potential target for therapeutic intervention. We designed a CD4 mutant (D1D2F43C) for site-specific coupling of compounds for screening against the cavity. Altogether, 81 cysteine-reactive compounds were designed, synthesized, and tested. Eight derivatives exceeded the affinity of native D1D2 for gp120. Structure-activity relationships (SAR) for derivatized CD4 binding to gp120 revealed significant plasticity of the Phe43 cavity and a narrow entrance. The primary contacts for compound recognition inside the cavity were found to be van der Waals interactions, whereas hydrophilic interactions were detected in the entrance. This first SAR on ligand binding to an interior cavity of gp120 may provide a starting point for structure-based assembly of small molecules targeting gp120-CD4 interaction.

subject areas

  • Acetamides
  • Antigens, CD4
  • Binding Sites
  • Binding, Competitive
  • Disulfides
  • Enzyme-Linked Immunosorbent Assay
  • HIV Envelope Protein gp120
  • HIV-1
  • Ligands
  • Models, Molecular
  • Mutation
  • Structure-Activity Relationship
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Identity

PubMed Central ID

  • PMC2532594

International Standard Serial Number (ISSN)

  • 0022-2623

Digital Object Identifier (DOI)

  • 10.1021/jm070564e

PubMed ID

  • 17803292
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Additional Document Info

start page

  • 4898

end page

  • 4908

volume

  • 50

issue

  • 20

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