ArticleJournal of the American Chemical Society2014
'Unconventional' coordination chemistry by metal chelating fragments in a metalloprotein active site.
Article in Journal of the American Chemical Society, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 22 citations in OpenAlex.
- Context-Dependent Functions of KDM6 Lysine Demethylases in Physiology and Disease.Advances in experimental medicine and biology · 2023Article
- Discovery of a Potent and Highly Selective Dipeptidyl Peptidase IV and Carbonic Anhydrase Inhibitor as "Antidiabesity" Agents Based on Repurposing and Morphing of WB-4101.Journal of medicinal chemistry · 2022Article
- Computational Prediction of the Binding Pose of Metal-Binding Pharmacophores.ACS medicinal chemistry letters · 2022Article
- Therapeutic Targeting of MMP-12 for the Treatment of Chronic Obstructive Pulmonary Disease.Journal of medicinal chemistry · 2020Article
- HTS by NMR for the Identification of Potent and Selective Inhibitors of Metalloenzymes.ACS medicinal chemistry letters · 2018Article
- Substituent Effects on the Coordination Chemistry of Metal-Binding Pharmacophores.Inorganic chemistry · 2017Article
- A Bioinorganic Approach to Fragment-Based Drug Discovery Targeting Metalloenzymes.Accounts of chemical research · 2017Article
- Effect of donor atom identity on metal-binding pharmacophore coordination.Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry · 2017Article
- Fragment-Based Approaches to the Development of Mycobacterium tuberculosis CYP121 Inhibitors.Journal of medicinal chemistry · 2016Article
- Histone demethylases in physiology and cancer: a tale of two enzymes, JMJD3 and UTX.Current opinion in genetics & development · 2016Review
- Methanethiol Binding Strengths and Deprotonation Energies in Zn(II)-Imidazole Complexes from M05-2X and MP2 Theories: Coordination Number and Geometry Influences Relevant to Zinc Enzymes.The journal of physical chemistry. B · 2015Article
- Exploring the influence of the protein environment on metal-binding pharmacophores.Journal of medicinal chemistry · 2014Article
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
Abstract
The binding of three closely related chelators: 5-hydroxy-2-methyl-4H-pyran-4-thione (allothiomaltol, ATM), 3-hydroxy-2-methyl-4H-pyran-4-thione (thiomaltol, TM), and 3-hydroxy-4H-pyran-4-thione (thiopyromeconic acid, TPMA) to the active site of human carbonic anhydrase II (hCAII) has been investigated. Two of these ligands display a monodentate mode of coordination to the active site Zn(2+) ion in hCAII that is not recapitulated in model complexes of the enzyme active site. This unprecedented binding mode in the hCAII-thiomaltol complex has been characterized by both X-ray crystallography and X-ray spectroscopy. In addition, the steric restrictions of the active site force the ligands into a 'flattened' mode of coordination compared with inorganic model complexes. This change in geometry has been shown by density functional computations to significantly decrease the strength of the metal-ligand binding. Collectively, these data demonstrate that the mode of binding by small metal-binding groups can be significantly influenced by the protein active site. Diminishing the strength of the metal-ligand bond results in unconventional modes of metal coordination not found in typical coordination compounds or even carefully engineered active site models, and understanding these effects is critical to the rational design of inhibitors that target clinically relevant metalloproteins.
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