Molecular Dynamics and Structural Studies of Zinc Chloroquine Complexes

ChemRxiv

Abstract

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.

Authors 17

1. Mirko Paulikat

   Forschungszentrum Jülich

   Affiliation as printed

   Forschungszentrum Jülich

2. Daniele Vitone

   University of Bari Aldo Moro

   Affiliation as printed

   University of Bari Aldo Moro

3. Florian Karl Schackert Aachen

   RWTH Aachen University · Forschungszentrum Jülich

   Affiliation as printed

   Forschungszentrum Jülich

   RWTH Aachen University

4. Nils Schuth

   Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional

   Affiliation as printed

   Center for Research and Advanced Studies of the National Polytechnic Institute

5. Alessandra Barbanente

   University of Bari Aldo Moro

   Affiliation as printed

   University of Bari Aldo Moro

6. GiovanniMaria Piccini

   Università della Svizzera italiana

   Affiliation as printed

   Università della Svizzera italiana

7. Emiliano Ippoliti

   Forschungszentrum Jülich

   Affiliation as printed

   Forschungszentrum Jülich

8. Giulia Rossetti Aachen

   RWTH Aachen University · Forschungszentrum Jülich

   Affiliation as printed

   Forschungszentrum Jülich

   RWTH Aachen University

9. Adam H. Clark

   Paul Scherrer Institute

   Affiliation as printed

   Paul Scherrer Institute

10. Maarten Nachtegaal

    Paul Scherrer Institute

    Affiliation as printed

    Paul Scherrer Institute

11. Michael Haumann

    Freie Universität Berlin

    Affiliation as printed

    Freie Universität Berlin

12. Holger Dau

    Freie Universität Berlin

    Affiliation as printed

    Freie Universität Berlin

13. Paolo Carloni Aachen

    RWTH Aachen University · Forschungszentrum Jülich

    Affiliation as printed

    Forschungszentrum Jülich

    RWTH Aachen University

14. Silvano Geremia

    University of Trieste

    Affiliation as printed

    University of Trieste

15. Rita De Zorzi

    University of Trieste

    Affiliation as printed

    University of Trieste

16. Liliana Quintanar

    Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional

    Affiliation as printed

    Center for Research and Advanced Studies of the National Polytechnic Institute

17. Fabio Arnesano

    University of Bari Aldo Moro

    Affiliation as printed

    University of Bari Aldo Moro