Fragment-Based Approaches to the Development of Mycobacterium tuberculosis CYP121 Inhibitors

Madeline Kavanagh, Anthony Coyne, Kirsty J McLean, Guy G James, Colin W Levy, Leonardo B Marino, Carvalho Luiz Pedro S De, Daniel Chan, Sean A Hudson, Sachin Surade, David Leys, Andrew W Munro & Christopher Abell
The essential enzyme CYP121 is a target for drug development against antibiotic resistant strains of Mycobacterium tuberculosis. A triazol-1-yl phenol fragment 1 was identified to bind to CYP121 using a cascade of biophysical assays. Synthetic merging and optimization of 1 produced a 100-fold improvement in binding affinity, yielding lead compound 2 (KD = 15 μM). Deconstruction of 2 into its component retrofragments allowed the group efficiency of structural motifs to be assessed, the identification of...
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