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Application of Fragment Screening and Merging to the Discovery of Inhibitors of the Mycobacterium tuberculosis Cytochrome P450 CYP121


  • We acknowledge funding from the EC (as part of the NM4TB project) and the BBSRC (grants BB/I019227/1 and BB/I019669/1 to C.A. and A.W.M., respectively). S.A.H. was supported by a Sir Mark Oliphant Cambridge Australia Scholarship awarded by the Cambridge Commonwealth Trust & Cambridge Overseas Trust, University of Cambridge. We give thanks to: Dr. J. Goodman (Cambridge) for assisting with the in silico calculations; Dr. J. E. Davies (Cambridge) for determining the small molecule crystal structure of the 1,5-diphenoltriazole 7; Dr. A. Boodhun (Cambridge) for performing mass spectrometry on recombinant His6-tagged CYP121; Dr. C. Levy (Manchester) for help with synchrotron data collection; Prof. T. L. Blundell (Cambridge) for helpful discussions.


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Pieces of the puzzle: The first fragment-based approach was used to target cytochrome P450 enzymes (CYPs) for drug development (see scheme). The experiments provide new insights into the binding site of the essential Mycobacterium tuberculosis CYP121 enzyme, and resulted in a promising novel lead compound based on fragment merging.