Fragment Library Screening to Discover Selective Inhibitors of a Key Microbial Enzyme

Fragment Library Screening to Discover Selective Inhibitors of a Key Microbial Enzyme

Bibliographic Details
Main Author: Gao, Geng
Language:English
Published: University of Toledo / OhioLINK 2010
Subjects:
Chemistry
ASADH
Fragment Library Screening
Inhibitor Development
Online Access:http://rave.ohiolink.edu/etdc/view?acc_num=toledo1290184812
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spelling ndltd-OhioLink-oai-etd.ohiolink.edu-toledo12901848122021-08-03T06:07:48Z Fragment Library Screening to Discover Selective Inhibitors of a Key Microbial Enzyme Gao, Geng Chemistry ASADH Fragment Library Screening Inhibitor Development The aspartate biosynthetic pathway, essential in plants and in most bacteria and fungi, produces the amino acids threonine, lysine, methionine, and isoleucine. The second step in the aspartate biosynthetic pathway is catalyzed by aspartate-β-semialdehyde dehydrogenase (ASADH). To treat the growing number of multidrug resistant organisms a new protocol is required to develop novel antibiotics. Fragment library screening provides a better hit rate and requires fewer resources, and our understanding of the catalytic mechanism of ASADH allows drug development to target this essential enzyme. Custom fragment libraries have been assembled and screened against ASADHs isolated from three different microbes. The initial hits from the libraries have good ligand efficiency and selectivity despite the similarity of the structures of those ASADHs and the in virtually identical active sites. Further development of the hits showed that amino acid analogues have both binding and chiral selectivity for the bacterial enzyme forms. Benzophenone analogues selectively inhibit the Gram-negative ASADH, while the fungal form of ASADH is only inhibited by small haloacids and substituted aromatic acids. Structural studies of enzyme-inhibitor complex are being carried out to guide further development of more potent and selective inhibitors. 2010 English text University of Toledo / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=toledo1290184812 http://rave.ohiolink.edu/etdc/view?acc_num=toledo1290184812 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws.
collection NDLTD
language English
sources NDLTD
topic Chemistry
ASADH
Fragment Library Screening
Inhibitor Development
spellingShingle Chemistry
ASADH
Fragment Library Screening
Inhibitor Development
Gao, Geng
Fragment Library Screening to Discover Selective Inhibitors of a Key Microbial Enzyme
author Gao, Geng
author_facet Gao, Geng
author_sort Gao, Geng
title Fragment Library Screening to Discover Selective Inhibitors of a Key Microbial Enzyme
title_short Fragment Library Screening to Discover Selective Inhibitors of a Key Microbial Enzyme
title_full Fragment Library Screening to Discover Selective Inhibitors of a Key Microbial Enzyme
title_fullStr Fragment Library Screening to Discover Selective Inhibitors of a Key Microbial Enzyme
title_full_unstemmed Fragment Library Screening to Discover Selective Inhibitors of a Key Microbial Enzyme
title_sort fragment library screening to discover selective inhibitors of a key microbial enzyme
publisher University of Toledo / OhioLINK
publishDate 2010
url http://rave.ohiolink.edu/etdc/view?acc_num=toledo1290184812
work_keys_str_mv AT gaogeng fragmentlibraryscreeningtodiscoverselectiveinhibitorsofakeymicrobialenzyme
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