Application of Fragment Growing and Fragment Linking to the Discovery of Inhibitors of Mycobacterium tuberculosis Pantothenate Synthetase


  • 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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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.