Thermodynamics of binding of a low-molecular-weight CD4 mimetic to HIV-1 gp120

Biochemistry. 2006 Sep 12;45(36):10973-80. doi: 10.1021/bi061193r.


NBD-556 and the chemically and structurally similar NBD-557 are two low-molecular weight compounds that reportedly block the interaction between the HIV-1 envelope glycoprotein gp120 and its receptor, CD4. NBD-556 binds to gp120 with a binding affinity of 2.7 x 10(5) M(-1) (K(d) = 3.7 muM) in a process characterized by a large favorable change in enthalpy partially compensated by a large unfavorable entropy change, a thermodynamic signature similar to that observed for binding of sCD4 to gp120. NBD-556 binding is associated with a large structuring of the gp120 molecule, as also demonstrated by CD spectroscopy. NBD-556, like CD4, activates the binding of gp120 to the HIV-1 coreceptor, CCR5, and to the 17b monoclonal antibody, which recognizes the coreceptor binding site of gp120. NBD-556 stimulates HIV-1 infection of CD4-negative, CCR5-expressing cells. The thermodynamic signature of the binding of NBD-556 to gp120 is very different from that of another viral entry inhibitor, BMS-378806. Whereas NBD-556 binds gp120 with a large favorable enthalpy and compensating unfavorable entropy changes, BMS-378806 does so with a small binding enthalpy change in a mostly entropy-driven process. NBD-556 is a competitive inhibitor of sCD4 and elicits a similar structuring of the coreceptor binding site, whereas BMS-378806 does not compete with sCD4 and does not induce coreceptor binding. These studies demonstrate that low-molecular-weight compounds can induce conformational changes in the HIV-1 gp120 glycoprotein similar to those observed upon CD4 binding, revealing distinct strategies for inhibiting the function of the HIV-1 gp120 envelope glycoprotein. Furthermore, competitive and noncompetitive compounds have characteristic thermodynamic signatures that can be used to guide the design of more potent and effective viral entry inhibitors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Anti-HIV Agents / metabolism*
  • Anti-HIV Agents / pharmacology
  • Binding Sites
  • Binding, Competitive
  • CD4 Antigens / drug effects
  • CD4 Antigens / metabolism*
  • Calorimetry / methods
  • Cell Line / drug effects
  • Cell Line / virology
  • Circular Dichroism
  • HIV Envelope Protein gp120 / chemistry
  • HIV Envelope Protein gp120 / metabolism*
  • HIV-1 / genetics
  • HIV-1 / pathogenicity
  • Humans
  • Molecular Mimicry*
  • Oxalates / metabolism*
  • Oxalates / pharmacology
  • Piperazines / metabolism
  • Piperazines / pharmacology
  • Piperidines / metabolism*
  • Piperidines / pharmacology
  • Protein Conformation
  • Receptors, CCR5 / drug effects
  • Receptors, CCR5 / metabolism
  • Thermodynamics*


  • Anti-HIV Agents
  • BMS-378806
  • CD4 Antigens
  • HIV Envelope Protein gp120
  • N-(4-bromophenyl)-N'-(2,2,6,6-tetramethylpiperidin-4-yl)oxalamide
  • N-(4-chlorophenyl)-N'-(2,2,6,6-tetramethylpiperidin-4-yl)oxalamide
  • Oxalates
  • Piperazines
  • Piperidines
  • Receptors, CCR5