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

Madeline E Kavanagh, Anthony G Coyne, Kirsty J McLean, Guy G James, Colin W Levy, Leonardo B Marino, Luiz Pedro S de Carvalho, Daniel S H Chan, Sean A Hudson, Sachin Surade, David Leys, Andrew W Munro, Chris Abell

    Research output: Contribution to journalArticlepeer-review


    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.

    Original languageEnglish
    Pages (from-to)3272-302
    Number of pages31
    JournalJournal of Medicinal Chemistry
    Issue number7
    Early online date22 Mar 2016
    Publication statusPublished - 14 Apr 2016

    Research Beacons, Institutes and Platforms

    • Biotechnology
    • Manchester Institute of Biotechnology


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