Abstract
In order to discover novel probes that may help in the investigation and control of infectious diseases through a new mechanism of action, we have evaluated a library of phenol-based natural products (NPs) for enzyme inhibition against four recently characterized pathogen β-family carbonic anhydrases (CAs). These include CAs from Mycobacterium tuberculosis, Candida albicans, and Cryptococcus neoformans as well as α-family human CA I and CA II for comparison. Many of the NPs selectively inhibited the mycobacterial and fungal β-CAs, with the two best performing compounds displaying submicromolar inhibition with a preference for fungal over human CA inhibition of more than 2 orders of magnitude. These compounds provide the first example of non-sulfonamide inhibitors that display β over α CA enzyme selectivity. Structural characterization of the library compounds in complex with human CA II revealed a novel binding mode whereby a methyl ester interacts via a water molecule with the active site zinc.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Anti-Bacterial Agents / chemical synthesis
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Anti-Bacterial Agents / chemistry
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Antifungal Agents / chemical synthesis
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Antifungal Agents / chemistry
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Biological Products / chemical synthesis
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Biological Products / chemistry*
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Candida albicans / enzymology*
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Carbonic Anhydrase I / antagonists & inhibitors
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Carbonic Anhydrase I / chemistry
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Carbonic Anhydrase II / antagonists & inhibitors
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Carbonic Anhydrase II / chemistry
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Carbonic Anhydrase Inhibitors / chemical synthesis
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Carbonic Anhydrase Inhibitors / chemistry*
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Carbonic Anhydrases / chemistry*
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Catalytic Domain
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Cryptococcus neoformans / enzymology*
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Crystallography, X-Ray
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Humans
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Hydrogen Bonding
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Isoenzymes / antagonists & inhibitors
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Isoenzymes / chemistry
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Models, Molecular
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Molecular Structure
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Mycobacterium tuberculosis / enzymology*
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Phenols / chemical synthesis
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Phenols / chemistry*
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Protein Binding
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Small Molecule Libraries
Substances
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Anti-Bacterial Agents
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Antifungal Agents
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Biological Products
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Carbonic Anhydrase Inhibitors
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Isoenzymes
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Phenols
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Small Molecule Libraries
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Carbonic Anhydrase I
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Carbonic Anhydrase II
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Carbonic Anhydrases