title: Effects of charge, volume, and surface on binding of inhibitor and substrate moieties to acetylcholinesterase.
abstract: 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.
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D001667:Binding, Competitive; D000440:Butanols / Q000378:metabolism; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002794:Choline / Q000031:analogs & derivatives / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000378:metabolism*; D004121:Dimethyl Sulfoxide / Q000378:metabolism; D000431:Ethanol / Q000031:analogs & derivatives / Q000378:metabolism*; D007700:Kinetics; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000378:metabolism; D013452:Sulfonium Compounds / Q000378:metabolism; D014297:Trimethylsilyl Compounds / Q000378:metabolism
chemical_list: D000440:Butanols; D002800:Cholinesterase Inhibitors; D013450:Sulfones; D013452:Sulfonium Compounds; D014297:Trimethylsilyl Compounds; C043885:2-(trimethylsilyl)ethanol; D000431:Ethanol; C046487:2-(methylsulfonyl)ethanol; C009352:sulfocholine; C009581:trimethylsulfonium; C025910:dimethyl sulfone; D000110:Acetylcholinesterase; D002794:Choline; D004121:Dimethyl Sulfoxide