Kinetic Characterization of Novel HIV-1 Entry Inhibitors: Discovery of a Relationship between Off-Rate and Potency

Molecules. 2018 Aug 3;23(8):1940. doi: 10.3390/molecules23081940.


The entry of HIV-1 into permissible cells remains an extremely attractive and underexploited therapeutic intervention point. We have previously demonstrated the ability to extend the chemotypes available for optimization in the entry inhibitor class using computational means. Here, we continue this effort, designing and testing three novel compounds with the ability to inhibit HIV-1 entry. We demonstrate that alteration of the core moiety of these entry inhibitors directly influences the potency of the compounds, despite common proximal and distal groups. Moreover, by establishing for the first time a surface plasmon resonance (SPR)-based interaction assay with soluble recombinant SOSIP Env trimers, we demonstrate that the off-rate (kd) parameter shows the strongest correlation with potency in an antiviral assay. Finally, we establish an underappreciated relationship between the potency of a ligand and its degree of electrostatic complementarity (EC) with its target, the Env complex. These findings not only broaden the chemical space in this inhibitor class, but also establish a rapid and simple assay to evaluate future HIV-1 entry inhibitors.

Keywords: HIV-1 Env; antiviral; bioisosteres; computer-aided drug design; surface plasmon resonance.

MeSH terms

  • Anti-HIV Agents / chemical synthesis
  • Anti-HIV Agents / chemistry*
  • Anti-HIV Agents / pharmacology
  • Cell Line
  • Cell Survival / drug effects
  • Drug Design
  • HIV Envelope Protein gp120 / metabolism
  • HIV-1 / drug effects*
  • HIV-1 / physiology
  • Humans
  • Kinetics
  • Molecular Docking Simulation
  • Piperazines / chemical synthesis
  • Piperazines / chemistry*
  • Piperazines / pharmacology
  • Protein Binding
  • Protein Multimerization
  • Pyrroles / chemical synthesis
  • Pyrroles / chemistry*
  • Pyrroles / pharmacology
  • Structure-Activity Relationship
  • Surface Plasmon Resonance
  • Triazoles / chemical synthesis
  • Triazoles / chemistry*
  • Triazoles / pharmacology
  • Virus Internalization / drug effects
  • env Gene Products, Human Immunodeficiency Virus / chemistry


  • Anti-HIV Agents
  • BMS-626529
  • HIV Envelope Protein gp120
  • Piperazines
  • Pyrroles
  • Triazoles
  • env Gene Products, Human Immunodeficiency Virus