Evaluation of substituted triazol-1-yl-pyrimidines as inhibitors of Bacillus anthracis acetohydroxyacid synthase

Title
Evaluation of substituted triazol-1-yl-pyrimidines as inhibitors of Bacillus anthracis acetohydroxyacid synthase
Authors
Vinayakumar GediKumaresan JayaramanSatish Kalme박효연박해철라임정한호규윤문영
Keywords
Acetohydroxyacid synthase; Bacillus anthracis; Docking; Reconstitution; Triazol-1-yl-pyrimidines
Issue Date
2010-06
Publisher
Biochimica et biophysica acta. Proteins and proteomics
Citation
VOL 1804, NO 6, 1369-1375
Abstract
Acetohydroxyacid synthase (AHAS), a potential target for antimicrobial agents, catalyzes the first common step in the biosynthesis of the branched-chain amino acids. The genes of both catalytic and regulatory subunits of AHAS from Bacillus anthracis (Bantx), a causative agent of anthrax, were cloned, overexpressed in Escherichia coli, and purified to homogeneity. To develop novel anti-anthracis drugs that inhibit AHAS, a chemical library was screened, and four chemicals, AVS2087, AVS2093, AVS2387, and AVS2236, were identified as potent inhibitors of catalytic subunit with IC50 values of 1.0±0.02, 1.0±0.04, 2.1±0.12, and 2.0±0.08 μM, respectively. Further, these four chemicals also showed strong inhibition against reconstituted AHAS with IC50 values of 0.05±0.002, 0.153±0.004, 1.30±0.10, and 1.29±0.40 μM, respectively. The basic scaffold of the AVS group consists of 1-pyrimidine-2-yl-1H-[1,2,4]triazole-3-sulfonamide. The potent inhibitor, AVS2093 showed the lowest binding energy, −8.52 kcal/mol and formed a single hydrogen bond with a distance of 1.973 . As the need for novel antibiotic classes to combat bacterial drug resistance increases, the screening of new compounds that act against Bantx-AHAS shows that AHAS is a good target for new anti-anthracis drugs.
URI
http://pubs.kist.re.kr/handle/201004/38778
ISSN
1570-9639
Appears in Collections:
KIST Publication > Article
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