Structure-based design and synthesis of highly potent SARS-CoV 3CL protease inhibitors

Chembiochem. 2007 Sep 24;8(14):1654-7. doi: 10.1002/cbic.200700254.

Abstract

In a successful example of lead optimization by computer modeling prediction, computational technology was used to optimize a lead inhibitor (TL‐3) of the SARS‐CoV 3CL protease. A novel C 2‐symmetric diol (1) was then designed and synthesized, and displayed higher affinity than the original lead compound by one order of magnitude in its inhibition constant (0.6→0.073 μm). We believe that this approach has provided a platform for further lead optimization.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Chemistry, Pharmaceutical / methods
  • Coronavirus 3C Proteases
  • Crystallization
  • Crystallography, X-Ray / methods
  • Cysteine Endopeptidases
  • Drug Design
  • Hydrogen Bonding
  • Ligands
  • Models, Chemical
  • Molecular Conformation
  • Protease Inhibitors / chemical synthesis*
  • Protease Inhibitors / pharmacology*
  • Protein Conformation
  • Severe acute respiratory syndrome-related coronavirus / enzymology*
  • Viral Proteins / antagonists & inhibitors*
  • X-Rays

Substances

  • Ligands
  • Protease Inhibitors
  • Viral Proteins
  • Cysteine Endopeptidases
  • Coronavirus 3C Proteases