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Interaction of chemically modified tetracyclines with catalytic Zn(II) ion in matrix metalloproteinase: evidence for metal coordination sites

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Abstract

Chemically modified tetracyclines (CMTs) have shown promising activity as matrix metalloproteinase (MMP) inhibitors acting as zinc-binding groups. The first step in the design of new and effective drugs is the molecular description of the mechanism of action in chemical and biological environments. In the present study, the structure and stability of [Zn(LH n )(H2O)2]2−x (n = 0, 1, 2 and x = −2, −1, 0) and [Zn(L)(His)3], where L represents five distinct, structurally related CMTs, are discussed. In addition to the effect of the ligand on Zn(II) coordination, the role of the solvent and pH was also determined. The results suggested that O1–Oam (labeled as site II in the present paper) of CMT-1, CMT-4 and CMT-7 was the most stable site in the gas phase and aqueous solution. However, for CMT-3 and CMT-8, coordination at the O11–O12 moiety (site VI) was preferred. This coordination site is an essential binding mode of CMTs with active zinc in the MMP catalytic site; therefore, our results support the singular behavior of CMT-3 and CMT-8 as promising MMP inhibitors.

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Acknowledgments

The authors thank the Conselho Nacional de Desenvolvimento Científico (CNPq—479682/2008-9) by the provision of the research concessions and for the financial support; and to Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG—CEX—APQ-00498-08) by the fomentation. B. L. Marcial also thanks to the CAPES for graduate fellowship.

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Authors and Affiliations

  1. Núcleo de Estudos em Química Computacional (NEQC), Departamento de Química, ICE, Universidade Federal de Juiz de Fora, Juiz de Fora, MG, 36036-330, Brazil

    Bruna L. Marcial, Luiz Antônio S. Costa & Hélio F. Dos Santos

  2. Laboratório de Química Computacional e Modelagem Molecular (LQC-MM), Departamento de Química, ICEx, Universidade Federal de Minas Gerais, Belo Horizonte, MG, 31270-901, Brazil

    Wagner B. De Almeida

  3. Departamento de Química, Universidade Federal de Lavras, Campus Universitário, 3037, Lavras, MG, 37200-000, Brazil

    Cleber P. A. Anconi

  4. Núcleo de Bioinformática de Juiz de Fora (NuBio-JF), Universidade Federal de Juiz de Fora, Juiz de Fora, MG, 36036-330, Brazil

    Hélio F. Dos Santos

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  1. Bruna L. Marcial
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  2. Luiz Antônio S. Costa
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Correspondence to Hélio F. Dos Santos.

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214_2010_881_MOESM1_ESM.doc

Optimized geometries of all complexes [Zn(LH n )(H2O)2]2−x (n = 0, 1, 2 and x = −2, −1, 0) are represented in Figs. S1–S2 for CMT-3 and Figs. S3–S4 for CMT-1. (DOC 2974 kb)

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Marcial, B.L., Costa, L.A.S., De Almeida, W.B. et al. Interaction of chemically modified tetracyclines with catalytic Zn(II) ion in matrix metalloproteinase: evidence for metal coordination sites. Theor Chem Acc 128, 377–388 (2011). https://doi.org/10.1007/s00214-010-0881-9

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