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This research was supported by the Bill & Melinda Gates Foundation. We are also grateful for funding from the Agency for Science Technology and Research (A*star) Singapore (PhD sponsorship, A.W.H.), the Fundacao para a Ciencia e Tecnologia (FCT; PhD sponsorship, H.L.S.), and Homerton College (Junior Research Fellowship to A.C.).
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Communication
Application of Fragment Growing and Fragment Linking to the Discovery of Inhibitors of Mycobacterium tuberculosis Pantothenate Synthetase†
Article first published online: 24 SEP 2009
DOI: 10.1002/anie.200903821
Copyright © 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Additional Information
How to Cite
Hung, A., Silvestre, H., Wen, S., Ciulli, A., Blundell, T. and Abell, C. (2009), Application of Fragment Growing and Fragment Linking to the Discovery of Inhibitors of Mycobacterium tuberculosis Pantothenate Synthetase. Angewandte Chemie International Edition, 48: 8452–8456. doi: 10.1002/anie.200903821
- †
Publication History
- Issue published online: 20 OCT 2009
- Article first published online: 24 SEP 2009
- Manuscript Received: 13 JUL 2009
Funded by
- Bill & Melinda Gates Foundation
- Agency for Science Technology and Research (A*star)
Keywords:
- drug design;
- fragment linking;
- inhibitors;
- tuberculosis;
- X-ray diffraction
Graphical Abstract
Two distinct strategies uncovered potent inhibitors of the title enzyme. X-ray crystallography and isothermal titration calorimetry guided the systematic elaboration of fragments identified from biophysical screens. The excellent inhibitor shown in the enzyme active site on the right was formed by connection of the lead fragments (left) with an acyl sulfonamide linker and resembles the best inhibitor discovered by the fragment-growing strategy.