Fragment-Based Approaches to the Development of Mycobacterium tuberculosis CYP121 Inhibitors
† Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, U.K.
‡ Centre for Synthetic Biology of Fine and Specialty Chemicals (SYNBIOCHEM), Manchester Institute of Biotechnology, Faculty of Life Sciences, University of Manchester, 131 Princess Street, Manchester M1 7DN, U.K.
§ Laboratory of Mycobacterial Metabolism and Antibiotic Research, Francis Crick Institute, The Mill Hill Laboratory, London NW7 1AA, U.K.
∥ School of Pharmaceutical Sciences, São Paulo State University (UNESP), 4801-902 Araraquara, SP, Brazil
⊥ Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA U.K.
J. Med. Chem., 2016, 59 (7), pp 3272–3302
DOI: 10.1021/acs.jmedchem.6b00007
Publication Date (Web): March 22, 2016
Copyright © 2016 American Chemical Society
Abstract
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.
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jmedchem.6b00007. Additional data related to this publication is available at the University of Cambridge data repository: https://www.repository.cam.ac.uk/handle/1810/254048
- X-ray crystallographic data tables, ligand density maps, human P450 inhibition data, and additional native mass spectrometry data (PDF)
- Molecular formula strings (CSV)
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