| Structural highlights
Publication Abstract from PubMed
The t-RNA-(N1G37) methyl transferase (TrmD) is essential for growth and highly conserved in both Gram-positive and Gram-negative bacterial pathogens. Additionally, TrmD is very distinct from its human ortholog TRM5, and thus is a suitable target for the design of novel antibacterials. Screening of a collection of compound fragments using Haemophilus influenzae TrmD identified inhibitory, fused thieno-pyrimidones that were competitive with S-adenosylmethionine (SAM), the physiological methyl donor substrate. Guided by x-ray co-crystal structures, fragment 1 was elaborated into a nanomolar inhibitor of a broad range of Gram-negative TrmD isozymes. These compounds demonstrated no activity against representative human SAM utilizing enzymes, PRMT1 and SET7/9. This is the first report of selective, nanomolar inhibitors of TrmD with demonstrated ability to order the TrmD lid in the absence of tRNA.
Selective Inhibitors of Bacterial t-RNA-(NG37) Methyltransferase (TrmD) that Demonstrate Novel Ordering of the Lid Domain.,Hill PJ, Abibi A, Albert R, Andrews B, Gagnon MM, Gao N, Grebe T, Hajec LI, Huang J, Livchak S, Lahiri SD, McKinney DC, Thresher J, Wang H, Olivier N, Buurman ET J Med Chem. 2013 Aug 27. PMID:23981144[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
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References
- ↑ Hill PJ, Abibi A, Albert R, Andrews B, Gagnon MM, Gao N, Grebe T, Hajec LI, Huang J, Livchak S, Lahiri SD, McKinney DC, Thresher J, Wang H, Olivier N, Buurman ET. Selective Inhibitors of Bacterial t-RNA-(NG37) Methyltransferase (TrmD) that Demonstrate Novel Ordering of the Lid Domain. J Med Chem. 2013 Aug 27. PMID:23981144 doi:10.1021/jm400718n
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