MULTICONFORMATIONAL MINIMAL STERIC DIFFERENCE - STRUCTURE-ACETYLCHOLINESTERASE HYDROLYSIS RATES RELATIONS FOR ACETIC-ACID ESTERS

This note presents the multiconformational MTD method and its applicat ion in a QSAR for acetylcholinesterase catalysed hydrolysis rates of a series of 25 acetic acid esters. Multiconformational MTD allows consi deration of molecules with several low energy conformations, as the mo stly aliphatic alcohol esters of this series, for QSAR. Conformations were selected for the QSAR study according to their energies calculate d by the COSMIC modelling program. Information from an X-ray crystallo graphy study, together with results of conformational energy calculati ons was used in constructing the hypermolecule for the 25 acetic acid ester molecules. A classical Hansch QSAR, with sigma-Taft constants, pi-hydrophobicities and E(s)-steric constants yields r(2) = 0.779 and r(CV)(2) = 0.577 in a crossvalidation procedure. The multiconformation al MTD, with sigma and MTD as structural parameters yields, for the c orelational equation r(2) = 0.868 and r(CV)(2) = 0.661 in a cross vali dation procedure. Both correlational equations indicate an appreciable positive effect of electron withdrawing eater groups. The optimised r eceptor map indicates a receptor cavity with certain similarities to a cetylcholine, but somewhat larger. QSAR studies are able, thus, to yie ld supplementary details to those given by X-ray studies.