Significance Zinc deficiency in the human population, a major public health concern, can also be a consequence of nutritional deficiency in protein uptake. The discovery that tryptophan metabolites 3-hydroxykynurenine and xanthurenic acid are major zinc-binding ligands in insect cells establishes the kynurenine pathway as a regulator of systemic zinc homeostasis. Many biological processes influenced by zinc and the kynurenine pathway, including the regulation of innate and acquired immune responses to viral infections, have not been studied in light of the direct molecular links revealed in this study.

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Chloroquine (CQ) is a first-choice drug against malaria and autoimmune diseases. It has been co-administered with zinc against SARS-CoV-2 and soon dismissed because of safety issues. The structural features of Zn−CQ complexes and the effect of CQ on zinc distribution in cells are poorly known. In this study, state-of-the-art computations combined with experiments were leveraged to solve the structural determinants of zinc−CQ interactions in solution and the solid state. NMR, ESI-MS, and X-ray absorption and diffraction methods were combined with ab initio molecular dynamics calculations to address the kinetic lability of this complex. Within the physiological pH range, CQ binds Zn 2+ through the quinoline ring nitrogen, forming [Zn(CQH)-Cl x (H 2 O) 3−x ] (3+)−x (x = 0, 1, 2, and 3) tetrahedral complexes. The Zn(CQH)Cl 3 species is stable at neutral pH and at high chloride concentrations typical of the extracellular medium, but metal coordination is lost at a moderately low pH as in the lysosomal lumen. The pentacoordinate complex [Zn(CQH)(H 2 O) 4 ] 3+ may exist in the absence of chloride. This in vitro/in silico approach can be extended to other metal-targeting drugs and bioinorganic systems.

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.

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.