Automated docking with protein flexibility in the design of femtomolar "click chemistry" inhibitors of acetylcholinesterase

J Chem Inf Model. 2013 Apr 22;53(4):898-906. doi: 10.1021/ci300545a. Epub 2013 Mar 29.


The use of computer-aided structure-based drug design prior to synthesis has proven to be generally valuable in suggesting improved binding analogues of existing ligands. Here we describe the application of the program AutoDock to the design of a focused library that was used in the "click chemistry in-situ" generation of the most potent noncovalent inhibitor of the native enzyme acetylcholinesterase (AChE) yet developed (K(d) = ~100 fM). AutoDock version 3.0.5 has been widely distributed and successfully used to predict bound conformations of flexible ligands. Here, we also used a version of AutoDock which permits additional conformational flexibility in selected amino acid side chains of the target protein.

Publication types

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

MeSH terms

  • Acetylcholinesterase / chemistry*
  • Binding Sites
  • Cholinesterase Inhibitors / chemistry*
  • Click Chemistry
  • Computer-Aided Design
  • Drug Design*
  • Humans
  • Ligands
  • Molecular Docking Simulation*
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • Small Molecule Libraries / chemistry*
  • Software*


  • Cholinesterase Inhibitors
  • Ligands
  • Small Molecule Libraries
  • Acetylcholinesterase