acs.jmedchem.6b00007.pdf (3.26 MB)

Fragment-based approaches to the development of Mycobacterium tuberculosis CYP121 inhibitors

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journal contribution
posted on 12.08.2020, 13:29 by Madeline E Kavanagh, Anthony G Coyne, Kirsty J McLean, Guy G James, Colin W Levy, Leonardo B Marino, Luiz Pedro S de Carvalho, Daniel SH Chan, Sean A Hudson, Sachin Surade, David Leys, Andrew W Munro, Chris 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 more LE scaffolds for optimization and highlighted binding affinity hotspots. Structure-guided addition of a metal-binding pharmacophore onto LE retrofragment scaffolds produced low nanomolar (KD = 15 nM) CYP121 ligands. Elaboration of these compounds to target binding hotspots in the distal active site afforded compounds with excellent selectivity against human drug-metabolizing P450s. Analysis of the factors governing ligand potency and selectivity using X-ray crystallography, UV-vis spectroscopy, and native mass spectrometry provides insight for subsequent drug development.