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

Academic Article
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Overview

authors

  • Morris, G. M.
  • Green, L. G.
  • Radic, Z.
  • Taylor, P.
  • Sharpless, K. Barry
  • Olson, Arthur
  • Grynszpan, F.

publication date

  • 2013

journal

  • Journal of Chemical Information and Modeling  Journal

abstract

  • 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.

subject areas

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

PubMed Central ID

  • PMC3698963

International Standard Serial Number (ISSN)

  • 1549-9596

Digital Object Identifier (DOI)

  • 10.1021/ci300545a

PubMed ID

  • 23451944
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Additional Document Info

start page

  • 898

end page

  • 906

volume

  • 53

issue

  • 4

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