Substrate Fragmentation for the Design of M. tuberculosis CYP121 Inhibitors

Madeline Kavanagh, Janine L Gray, Sophie H Gilbert, Anthony Coyne, Kirsty J McLean, Holly J Davis, Andrew W Munro & Christopher Abell
The cyclo-dipeptide substrates of the essential M. tuberculosis (Mtb) enzyme CYP121 were deconstructed into their component fragments and screened against the enzyme. A number of hits were identified, one of which exhibited an unexpected inhibitor-like binding mode. The inhibitory pharmacophore was elucidated, and fragment binding affinity was rapidly improved by synthetic elaboration guided by the structures of CYP121 substrates. The resulting inhibitors have low micromolar affinity, good predicted physicochemical properties and selectivity for CYP121 over other...
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