Conformational analysis of ticagrelor: effect of noncovalent interaction on conformational population

In order to track the source of duplicated peaks in the H-1-NMR spectrum of Ticagrelor, variable-temperature NMR (VT-NMR) experiment was carried out with temperature increasing from 300 to 343K. The result showed that the phenomenon was brought forth by coexistence of conformational isomers. Subsequently, conformational search was carried out by molecular mechanics (MM) stimulations associating with quantum mechanics (QM) calculations. The results revealed that the isomers resulting in duplicated proton peaks were introduced by the rotation of 2,4-diflurophenyl group on C(3')position of cyclopropyl. Finally, noncovalent interaction (NCI) topological analysis of the conformers exhibited that CH- interactions and H-bonds play important roles in controlling the population of conformers of ticagrelor.