Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 59, Issue 7, Pages 3272-3302Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.6b00007
Keywords
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Funding
- Commonwealth (University of Cambridge) Scholarship
- Cambridge Overseas Trust
- BBSRC [BB/I019669/1, BB/I019227/1]
- Ogden Trust
- Isaac Newton Trust
- Croucher Cambridge International Scholarship
- Oliphant Cambridge Australia Scholarship - Cambridge Commonwealth Trust [10132070]
- Francis Crick Institute
- Wellcome Trust
- Cancer Research UK
- UK Medical Research Council [MC_UP_A253_1111]
- FAPESP
- CNPq
- CAPES-PDSE [2011/21232-1, 140079/2013-0, 99999.003125/2014-09]
- Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [11/21232-1] Funding Source: FAPESP
- Biotechnology and Biological Sciences Research Council [BB/I019227/1, BB/I019669/1] Funding Source: researchfish
- Engineering and Physical Sciences Research Council [EP/K039520/1] Funding Source: researchfish
- Medical Research Council [MC_UP_A253_1111] Funding Source: researchfish
- The Francis Crick Institute [10060] Funding Source: researchfish
- BBSRC [BB/I019669/1, BB/I019227/1] Funding Source: UKRI
- EPSRC [EP/K039520/1] Funding Source: UKRI
- MRC [MC_UP_A253_1111] Funding Source: UKRI
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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 (K-D = 15 mu M). 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 (K-D = 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.
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