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Application of Fragment Growing and Fragment Linking to the Discovery of Inhibitors of Mycobacterium tuberculosis Pantothenate Synthetase
Author(s) -
Hung Alvin W.,
Silvestre H. Leonardo,
Wen Shijun,
Ciulli Alessio,
Blundell Tom L.,
Abell Chris
Publication year - 2009
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.200903821
Subject(s) - fragment (logic) , isothermal titration calorimetry , enzyme , mycobacterium tuberculosis , linker , chemistry , biochemistry , stereochemistry , tuberculosis , medicine , computer science , pathology , programming language , operating system
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.