Field-Based Affinity Optimization of a Novel Azabicyclohexane Scaffold HIV-1 Entry Inhibitor

Molecules. 2019 Apr 22;24(8):1581. doi: 10.3390/molecules24081581.


Small-molecule HIV-1 entry inhibitors are an extremely attractive therapeutic modality. We have previously demonstrated that the entry inhibitor class can be optimized by using computational means to identify and extend the chemotypes available. Here we demonstrate unique and differential effects of previously published antiviral compounds on the gross structure of the HIV-1 Env complex, with an azabicyclohexane scaffolded inhibitor having a positive effect on glycoprotein thermostability. We demonstrate that modification of the methyltriazole-azaindole headgroup of these entry inhibitors directly effects the potency of the compounds, and substitution of the methyltriazole with an amine-oxadiazole increases the affinity of the compound 1000-fold over parental by improving the on-rate kinetic parameter. These findings support the continuing exploration of compounds that shift the conformational equilibrium of HIV-1 Env as a novel strategy to improve future inhibitor and vaccine design efforts.

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
  • HEK293 Cells
  • HIV Envelope Protein gp120 / metabolism*
  • HIV Infections / drug therapy
  • HIV Infections / metabolism
  • HIV Infections / pathology
  • HIV-1 / metabolism*
  • Humans
  • Molecular Docking Simulation
  • Structure-Activity Relationship
  • Virus Internalization / drug effects*


  • Anti-HIV Agents
  • HIV Envelope Protein gp120