Effects of charge, volume, and surface on binding of inhibitor and substrate moieties to acetylcholinesterase

J Med Chem. 1985 Sep;28(9):1309-13. doi: 10.1021/jm00147a033.


Reversible inhibitors for acetylcholinesterase, AcChE, have been studied. Sterically similar alcohols with tetra-substituted uncharged beta groups, (CH3)3SiCH2CH2OH (I), (CH3)3CCH2CH2OH (IA), and CH3S(O2)CH2CH2OH (VII), bind similarly, KI = 3-9 mM, and each binds similarly to its acetate substrate; cationic analogues, (CH3)3N+CH2CH2OH (IB) and (CH3)2S+CH2CH2OH (II), bind similarly to each other, KI = 0.4 mM, similar to Km values of their acetate substrates, and more strongly than the uncharged alcohols by approximately 1.5 kcal/mol. In comparisons of VII with CH3SO2CH3, II with (CH3)3S+, and IB with (CH3)4N+, hydroxyethyl leads to more favorable binding than methyl by approximately 0.8 kcal/mol, despite lower hydrophobicity. Two hydrophobic methyl groups, in comparison of IA with butanol, and two hydrophilic sulfone O atoms, in comparison of VII with 2-(methylthio)ethanol, increase binding similarly, by 1.0 kcal/mol. Conversion of (CH3)3S+ to (CH3)3S+O also improves binding. However, (CH3)3N+O- does not bind to AcChE, and conversion of 1-(dimethylammonio)-4-pentanone and 2-(dimethylammonio)ethyl acetate to their N-oxides, changes of identical to N+H to identical to N+--O-, decreases binding by 1.5 kcal/mol. Although the -COCH3 group in esters with well-binding beta substituents makes essentially no contribution to binding over that of the alcohols, in esters with weakly bound beta substituents, (CH3)2N+(O-), CH3N+H2, CH3S(O), CH3CH2, and CH3S binding is dominated by the ester -COCH3 group, with values of Km approximately 16 mM.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acetylcholinesterase / metabolism*
  • Binding, Competitive
  • Butanols / metabolism
  • Chemical Phenomena
  • Chemistry, Physical
  • Choline / analogs & derivatives
  • Choline / metabolism
  • Cholinesterase Inhibitors / metabolism*
  • Dimethyl Sulfoxide / metabolism
  • Ethanol / analogs & derivatives
  • Ethanol / metabolism*
  • Kinetics
  • Structure-Activity Relationship
  • Sulfones / metabolism
  • Sulfonium Compounds / metabolism
  • Trimethylsilyl Compounds / metabolism


  • Butanols
  • Cholinesterase Inhibitors
  • Sulfones
  • Sulfonium Compounds
  • Trimethylsilyl Compounds
  • 2-(trimethylsilyl)ethanol
  • Ethanol
  • 2-(methylsulfonyl)ethanol
  • sulfocholine
  • trimethylsulfonium
  • dimethyl sulfone
  • Acetylcholinesterase
  • Choline
  • Dimethyl Sulfoxide