Fragment-Based Approaches to the Development of Mycobacterium tuberculosis CYP121 Inhibitors
Authors
McLean, Kirsty J
James, Guy G
Levy, Colin W
Marino, Leonardo B
de, Carvalho Luiz Pedro S
Chan, Daniel
Hudson, Sean A
Surade, Sachin
Leys, David
Munro, Andrew W
Publication Date
2016-03-22Journal Title
Journal of Medicinal Chemistry
ISSN
0022-2623
Publisher
American Chemical Society
Volume
59
Pages
3272-3302
Language
English
Type
Article
Metadata
Show full item recordCitation
Kavanagh, M., Coyne, A., McLean, K. J., James, G. G., Levy, C. W., Marino, L. B., de, C. L. P. S., et al. (2016). Fragment-Based Approaches to the Development of Mycobacterium tuberculosis CYP121 Inhibitors. Journal of Medicinal Chemistry, 59 3272-3302. https://doi.org/10.1021/acs.jmedchem.6b00007
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.
Keywords
cytochrome P450, CYP121, mycobacterium tuberculosis, fragment-based drug discovery, retrofragment, group efficiency
Relationships
Sponsorship
MEK was supported by a Commonwealth (University of Cambridge) Scholarship awarded in conjunction with the Cambridge Commonwealth Trust and Cambridge Overseas Trust. AGC and KJM were supported by grants from the BBSRC (Grant No: BB/I019669/1 and BB/I019227/1). GGJ received funding from the Ogden Trust and the Isaac Newton Trust administered through the University of Cambridge Bursary Scheme. DSCH was supported by a Croucher Cambridge International Scholarship awarded in conjunction between the Croucher Foundation and the Cambridge Overseas Trust. SAH was supported by an Oliphant Cambridge Australia Scholarship (App No: 10132070) awarded by the Cambridge Commonwealth Trust. The contributions of LBM and LPSC were supported by funds from the Francis Crick Institute, which receives its core funding principally from Wellcome Trust, Cancer Research UK, and the UK Medical Research Council (to LPSC - MC_UP_A253_1111) and funds from FAPESP, CNPq and CAPES-PDSE (to LBM - 2011/21232-1, 140079/2013-0, 99999.003125/2014-09).
Funder references
BBSRC (BB/I019669/1)
EPSRC (EP/K039520/1)
Embargo Lift Date
2050-01-01
Identifiers
External DOI: https://doi.org/10.1021/acs.jmedchem.6b00007
This record's URL: https://www.repository.cam.ac.uk/handle/1810/254343
Rights
Creative Commons Attribution 4.0 International
Licence URL: http://creativecommons.org/licenses/by/4.0/
Recommended or similar items
The following licence files are associated with this item: