Molecular Dynamics and Structural Studies of Zinc Chloroquine Complexes

Chloroquine (CQ) is a first-choice drug against malaria and autoimmune diseases. It may act as a zinc ionophore. In this study, state-of-the-art computations and experiments were leveraged to solve the structure of the Zn chloride-CQ complex in solution and in solid state. The integration of different techniques (NMR, ESI-MS, X-ray absorption and diffraction methods) together with ab initio molecular dynamics simulations, overcomes the issues related to the kinetic lability of zinc complexes. Within the physiological pH range, CQ binds Zn2+ through the quinoline ring nitrogen, forming [Zn(CQH)Clx(H2O)3–x](3+)–x (x = 0, 1, 2, 3) tetrahedral complexes. The Zn(CQH)Cl3 species is stable at neutral pH and at high chloride concentrations typical of the extracellular medium, but metal coordination is lost at moderately low pH, suggesting the release of Zn2+ ions into the lysosomal lumen. [Zn(CQH)(H2O)4]3+ may exist in the absence of chloride. This in vitro / in silico approach can be extended to other metal-targeting drugs and and bioinorganic systems.