Bidentate Zinc Chelators for α‐Carbonic Anhydrases that Produce a Trigonal Bipyramidal Coordination Geometry

Wischeler, Johannes Schulze; Innocenti, Alessio; Vullo, Daniela; Agrawal, Arpita; Cohen, Seth M.; Heine, A.; Supuran, Claudiu T.; Klebe, G.

doi:10.1002/cmdc.201000200

Cited by 30 publications

(25 citation statements)

References 38 publications

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“…The crystal structure of hCAII L198G with 1,2-HOPTO bound (1.42 Å resolution) shows the MBP does not change its binding geometry when compared to the same compound bound in wild type hCAII (Figure 5, PDB:3M1K) [37]. In both enzymes, 1,2-HOPTO is bound in a bidentate fashion to the Zn(II) ion, with Zn-S and Zn-O bond distances of ~2.4 Å to ~2.6 Å creating a 5-coordinate species at the metal center with a trigonal bipyramidal geometry.…”

Section: Resultsmentioning

confidence: 99%

Effect of donor atom identity on metal-binding pharmacophore coordination

et al. 2017

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The inhibition and binding of three metal-binding pharmacophores (MBPs), 2-hydroxycyclohepta-2,4,6-trien-1-one (tropolone), 2-mercaptopyridine-N-oxide (1,2-HOPTO), and 2-hydroxycyclohepta-2,4,6-triene-1-thione (thiotropolone) to human carbonic anhydrase II (hCAII) and a mutant protein hCAII L198G were investigated. These MBPs displayed bidentate coordination to the active site Zn(II) metal ion, but the MBPs respond to the mutation of L198G differently, as characterized by inhibition activity assays and X-ray crystallography. The L198G mutation increases the active site volume thereby decreasing the steric pressure exerted on MBPs upon binding, allowing changes in MBP coordination to be observed. When comparing the binding mode of tropolone to thiotropolone or 1,2-HOPTO (O,O versus O,S donor sets), structural modifications of the hCAII active site were shown to have a stronger effect on MBPs with an O,O versus O,S donor set. These findings were corroborated with density functional theory (DFT) calculations of model coordination complexes. These results suggest that the MBP binding geometry is a malleable interaction, particularly for certain ligands, and that the identity of the donor atoms still play a significant role in ligand coordination. Understanding underlying interactions between a MBP and a metalloenzyme active site may aid in the design and development of potent metalloenzyme inhibitors.

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Section: Resultsmentioning

confidence: 99%

Effect of donor atom identity on metal-binding pharmacophore coordination

et al. 2017

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“…53 Finally, resorcinol ( 3 ) has been shown to inhibit hCAII by hydrogen bonding to the Zn(II)-bound hydroxide, and does not engage in metal ion binding. 54 Inhibition constants and previously reported binding modes for these molecules are summarized in Table 2.…”

Section: Effect Of Coordination Environment On Inhibitor Binding Geommentioning

confidence: 99%

Metalloprotein–Inhibitor Binding: Human Carbonic Anhydrase II as a Model for Probing Metal–Ligand Interactions in a Metalloprotein Active Site

2013

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An ever increasing number of metalloproteins are being discovered that play essential roles in physiological processes. Inhibitors of these proteins have significant potential for the treatment of human disease, but clinical success of these compounds has been limited. Herein, Zn(II)-dependent metalloprotein inhibitors in clinical use are reviewed, and the potential for using novel metal-binding groups (MBGs) in the design of these inhibitors is discussed. By using human carbonic anhydrase II (hCAII) as a model system, the nuances of MBG-metal interactions in the context of a protein environment can be probed. Understanding how metal coordination influences inhibitor binding may help in the design new therapeutics targeting metalloproteins.

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“…[1][2][3][4] All the zinc binders known so far (organic compounds) coordinate monodentately to the zinc ion through a nitrogen atom from the zinc-binding group (ZBG), 7-10 whereas few bidentate inhibitors have been discovered, such as a thiomalthol anlogue (HOPTO) 11 and N-hydroxyurea 12 which were shown to coordinate bidentately to the Zn(II) ion from the enzyme active site. Dithiocarbamates (DTCs) are well known metal complexing agents and they also possess interesting biomedical and agricultural applications.…”

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confidence: 99%