Spin State of Chloroquine-Heme Complexes: Formation of a Hemin Tetramer Adduct

Abstract

Complex formation between the antimalarial drug chloroquine and its presumed target ferriprotoporphyrin IX in three different solutions (pH 6.5, pH 9, and in a water methanol mixture) is characterized by nuclear magnetic resonance, UV spectroscopy, and mass spectrometry. NMR paramagnetic relaxation measurements are used to derive intermolecular distances between the molecules and model structures of the complexes are calculated by molecular dynamics simulations. Observation of an unusual spin state in NMR measurements leads to the postulation of a novel 4:2 stoichiometry of the complex, which is supported by mass spectrometry and UV spectroscopy.