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

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Abstract
Reversible inhibitors for acetylcholinesterase, AcChE, have been studied. Sterically similar alcohols with tetrasubstituted uncharged .beta. groups, (CH3)3SiCH2CH2OH2OH (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 .apprx. 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 .apprx. 0.8 kcal/mol, despite lower hydrophobicity. Two hydrophobic methyl groups, in comparison of IA with butanol, with two hydrophilic sulfone 0 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 .tbd.N+H to .tbd.N+.sbd.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 .apprx. 16 mM.