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 Zn2+ through the quinoline ring nitrogen, forming [Zn(CQH)Clx(H2O)3-x](3+)-x (x = 0, 1, 2, and 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 a moderately low pH as in the lysosomal lumen. The pentacoordinate complex [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 bioinorganic systems.

Molecular Dynamics and Structural Studies of Zinc Chloroquine Complexes / Paulikat, M.; Vitone, D.; Schackert, F. K.; Schuth, N.; Barbanente, A.; Piccini, G.; Ippoliti, E.; Rossetti, G.; Clark, A. H.; Nachtegaal, M.; Haumann, M.; Dau, H.; Carloni, P.; Geremia, S.; De Zorzi, R.; Quintanar, L.; Arnesano, F.. - In: JOURNAL OF CHEMICAL INFORMATION AND MODELING. - ISSN 1549-9596. - 63:1(2023), pp. 161-172. [10.1021/acs.jcim.2c01164]

Molecular Dynamics and Structural Studies of Zinc Chloroquine Complexes

Piccini G.;
2023

Abstract

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 Zn2+ through the quinoline ring nitrogen, forming [Zn(CQH)Clx(H2O)3-x](3+)-x (x = 0, 1, 2, and 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 a moderately low pH as in the lysosomal lumen. The pentacoordinate complex [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 bioinorganic systems.
2023
63
1
161
172
Molecular Dynamics and Structural Studies of Zinc Chloroquine Complexes / Paulikat, M.; Vitone, D.; Schackert, F. K.; Schuth, N.; Barbanente, A.; Piccini, G.; Ippoliti, E.; Rossetti, G.; Clark, A. H.; Nachtegaal, M.; Haumann, M.; Dau, H.; Carloni, P.; Geremia, S.; De Zorzi, R.; Quintanar, L.; Arnesano, F.. - In: JOURNAL OF CHEMICAL INFORMATION AND MODELING. - ISSN 1549-9596. - 63:1(2023), pp. 161-172. [10.1021/acs.jcim.2c01164]
Paulikat, M.; Vitone, D.; Schackert, F. K.; Schuth, N.; Barbanente, A.; Piccini, G.; Ippoliti, E.; Rossetti, G.; Clark, A. H.; Nachtegaal, M.; Haumann, M.; Dau, H.; Carloni, P.; Geremia, S.; De Zorzi, R.; Quintanar, L.; Arnesano, F.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/1330710
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