Identification of selective enzyme inhibitors by fragment library screening.
The microbial threat to human health is growing due to the dramatic increase in the number of multidrug-resistant organisms. The decline in effective antibiotics available to treat these growing threats has provided greater urgency to the search for new antibiotics. Clearly, new approaches must be developed against novel targets to control these resistant infectious organisms. The screening of low molecular weight compounds against new protein targets provides an opportunity to identify novel inhibitors as starting points for the development of new antibiotics. Custom fragment libraries have been assembled and screened against 3 representative forms of a key enzyme in an essential microbial biosynthetic pathway. Although each of these aspartate semialdehyde dehydrogenases (ASADHs) catalyzes the same reaction and each shares identical active site functional groups, subtle differences in enzyme structures have led to different binding selectivity among the initial hits from these fragment libraries. Amino acid analogues have been identified that show selectivity for either the gram-negative or gram-positive bacterial enzyme forms. A series of benzophenone analogues selectively inhibit the gram-negative ASADH, whereas some haloacids and substituted aromatic acids have been found to inhibit only the fungal form of ASADH. Each of these low molecular weight compounds possesses high ligand binding efficiency for their target enzyme forms. These results support the goal of designing lead compounds that will selectively target ASADHs from different microbial species.
Gao
Geng
G
Department of Chemistry, University of Toledo, Toledo, OH 43606, USA.
Liu
Xuying
X
Pavlovsky
Alexander
A
Viola
Ronald E
RE
D000596:Amino Acids / Q000032:analysis / Q000494:pharmacology; D001223:Aspartate-Semialdehyde Dehydrogenase / Q000037:antagonists & inhibitors*; D001577:Benzophenones / Q000032:analysis / Q000494:pharmacology; D055162:Biocatalysis / Q000187:drug effects; D002176:Candida albicans / Q000187:drug effects; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004791:Enzyme Inhibitors / Q000032:analysis* / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D054852:Small Molecule Libraries / Q000032:analysis* / Q000494:pharmacology*; D013296:Streptococcus pneumoniae / Q000187:drug effects; D013379:Substrate Specificity; D014734:Vibrio cholerae / Q000187:drug effects
D000596:Amino Acids; D001577:Benzophenones; D004791:Enzyme Inhibitors; D054852:Small Molecule Libraries; D001223:Aspartate-Semialdehyde Dehydrogenase