Multiconformational Minimal Steric Difference. Structure‐Acetylcholinesterase Hydrolysis Rates Relations for Acetic Acid Esters

Abstract

AbstractThis note presents the multiconformational MTD method and its application in a QSAR for acetylcholinesterase catalysed hydrolysis rates of a series of 25 acetic acid esters. Multiconformational MTD allows consideration of molecules with several low energy conformations, as the mostly aliphatic alcohol esters of this series, for QSAR. Conformations were selected for the QSAR study according to their energies calculated by the COSMIC modelling program. Information from an X‐ray crystallography study, together with results of conformational energy calculations was used in constructing the hypermolecule for the 25 acetic acid ester molecules. A classical Hansch QSAR, with σ*‐Taft constants, π‐hydrophobicities and Es‐steric constants yields r2 = 0.779 and r2cv = 0.577 in a crossvalidation procedure. The multiconformational MTD, with σ* and MTD as structural parameters yields, for the corelational equation r2 = 0.868 and r2cv = 0.661 in a cross validation procedure. Both correlational equations indicate an appreciable positive effect of electron withdrawing ester groups. The optimised receptor map indicates a receptor cavity with certain similarities to acetylcholine, but somewhat larger. QSAR studies are able, thus, to yield supplementary details to those given by X‐ray studies.