Modeling of the conformational flexibility and E/Z isomerism of thiazoximic acid and cefotaxime

Abstract

AbstractThe conformational flexibility of the Z and E isomers of cefotaxime (CFX) and thiazoximic acid, their ground‐state isomerization path and transition state, were all analyzed in depth. The modeling was carried at the semiempirical and DFT‐BLYP level with geometry optimization for gas phase conditions. That approach was used after a thorough analysis using classical molecular dynamics to initially define large families of conformers. The lowest energy conformers always have an E configuration, in contradiction to the behavior observed in solution, and the Z–E isomerization mechanism is a rotation. These results reveal the remarkable flexibility of these molecules, allow anticipating the role of water and of their target proteins in the redistribution of the conformers population, and provide the best geometry known for CFX. © 2011 Wiley Periodicals, Inc. Int J Quantum Chem, 2011