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.
Original language | English |
---|---|
Pages (from-to) | 1682-92 |
Number of pages | 11 |
Journal | Journal of Medicinal Chemistry |
Volume | 54 |
Issue number | 6 |
DOIs | |
Publication status | Published - 24 Mar 2011 |
Keywords
- Anti-Bacterial Agents
- Antifungal Agents
- Biological Agents
- Candida albicans
- Carbonic Anhydrase I
- Carbonic Anhydrase II
- Carbonic Anhydrase Inhibitors
- Carbonic Anhydrases
- Catalytic Domain
- Cryptococcus neoformans
- Crystallography, X-Ray
- Humans
- Hydrogen Bonding
- Isoenzymes
- Models, Molecular
- Molecular Structure
- Mycobacterium tuberculosis
- Phenols
- Protein Binding
- Small Molecule Libraries