More-powerful virus inhibitors from structure-based analysis of HEV71 capsid-binding molecules

Nat Struct Mol Biol. 2014 Mar;21(3):282-288. doi: 10.1038/nsmb.2769. Epub 2014 Feb 9.


Enterovirus 71 (HEV71) epidemics in children and infants result mainly in mild symptoms; however, especially in the Asia-Pacific region, infection can be fatal. At present, no therapies are available. We have used structural analysis of the complete virus to guide the design of HEV71 inhibitors. Analysis of complexes with four 3-(4-pyridyl)-2-imidazolidinone derivatives with varying anti-HEV71 activities pinpointed key structure-activity correlates. We then identified additional potentially beneficial substitutions, developed methods to reliably triage compounds by quantum mechanics-enhanced ligand docking and synthesized two candidates. Structural analysis and in vitro assays confirmed the predicted binding modes and their ability to block viral infection. One ligand (with IC50 of 25 pM) is an order of magnitude more potent than the best previously reported inhibitor and is also more soluble. Our approach may be useful in the design of effective drugs for enterovirus infections.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents / chemistry
  • Binding Sites
  • Capsid / chemistry*
  • Capsid Proteins / chemistry*
  • Chemistry, Pharmaceutical
  • Drug Design
  • Enterovirus A, Human / drug effects*
  • Enterovirus Infections / drug therapy
  • Enterovirus Infections / virology
  • Imidazoles / chemistry*
  • Inhibitory Concentration 50
  • Ligands
  • Protein Binding
  • Protein Conformation
  • Structure-Activity Relationship


  • Antiviral Agents
  • Capsid Proteins
  • Imidazoles
  • Ligands

Associated data

  • PDB/4CDQ
  • PDB/4CDU
  • PDB/4CDW
  • PDB/4CDX
  • PDB/4CEW
  • PDB/4CEY