Conformational analysis of Lidocaine by combined use of NMR Lanthilde-induced shifts and conformational energy calculations
Suki, Maimunah Mat
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The preferred conformation(s) of the local anesthetic molecule, lidocaine, were determined through the combined use of lanthanide-induced shifts (LIS) and conformational energy calculations. The procedure consisted of two parts: experimental (for the determination of observed LIS) and computational (for the determination of the conformations of the lowest energy and for the fitting of the calculated to observed LIS). The experimental procedure followed the incremental dilution method at constant substrate concentration, Sₒ, in which the initial solution has the highest value of molar ratio of lanthanide shift reagent (LSR) to lidocaine, Lₒ/Sₒ. The observed LIS was found from the slope of a linear least squares plot of the lanthanide-induced shift vs. Lₒ/Sₒ. The computational procedure consisted of the determination of the lowest energy conformations and the calculation of the theoretical LIS for pseudocontact interaction. In determining the possible conformations, the coordinates of the heavy atoms of the molecule from x-ray data were used in a computer program to generate the coordinates of the hydrogen atoms in the molecule. These coordinates were then transformed into a molecular coordinate system in which the atoms of the molecule were used to define the origin, positive x-axis and x-y plane. Ten subrotation angles were defined for the molecule. In the computer search for the lowest energy conformation(s), the subrotation angles were allowed to vary until a minimum molecular energy was reached. Another exploratory procedure for determining low energy conforma^ tions which was carried out was energy mapping around the "critical" subrotation angles 13, 15 and 16. Two possible conformations, called the 200° and 60° conformations, were obtained from the computer search. The angles given are the values of the dihedral angles N-C-C-N in the two energetically preferred conformations. The values of the other dihedral angles were essentially the same in each conformation. The LIS were then calculated and compared to the observed LIS previously obtained. The comparison resulted in a value termed as an agreement factor, AF. In the search for good AF values, the independent variables, alpha, (which defines the position of the lathanide atom in the complex), rho (the position of the z-magnetic axis) and f (the fraction of one of a pair of conformations), were varied by an iterative computer technique. The distance of the lanthanide atom from the binding site, oxygen, was kept at 2.7°A. The C=0....Eu angle was found to be in the range of 140° to 160° with the Eu binding at a site which places it nearer to the ethyl group of lidocaine and away from the aromatic ring.