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

Research output: Contribution to journalArticle

  • External authors:
  • Madeline E Kavanagh
  • Anthony G Coyne
  • Kirsty J McLean
  • Guy G James
  • Leonardo B Marino
  • Luiz Pedro S de Carvalho
  • Daniel S H Chan
  • Sean A Hudson
  • Sachin Surade
  • 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.

Bibliographical metadata

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