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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

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Kavanagh, Madeline E. [1] ; Coyne, Anthony G. [1] ; McLean, Kirsty J. [2] ; James, Guy G. [1] ; Levy, Colin W. [2] ; Marino, Leonardo B. [3, 4] ; de Carvalho, Luiz Pedro S. [3] ; Chan, Daniel S. H. [1] ; Hudson, Sean A. [1, 5] ; Surade, Sachin [6] ; Leys, David [2] ; Munro, Andrew W. [2] ; Abell, Chris [1]
Total Authors: 13
[1] Univ Cambridge, Dept Chem, Lensfield Rd, Cambridge CB2 1EW - England
[2] Univ Manchester, Ctr Synthet Biol Fine & Specialty Chem SYNBIOCHEM, Manchester Inst Biotechnol, Fac Life Sci, 131 Princess St, Manchester M1 7DN, Lancs - England
[3] Francis Crick Inst, Mill Hill Lab, Lab Mycobacterial Metab & Antibiot Res, London NW7 1AA - England
[4] Sao Paulo State Univ UNESP, Sch Pharmaceut Sci, BR-4801902 Araraquara, SP - Brazil
[5] Australian Natl Univ, Res Sch Chem, Coll Phys & Math Sci, Bldg 137, Sullivans Creek Rd, Canberra, ACT 0200 - Australia
[6] Univ Cambridge, Dept Biochem, 80 Tennis Court Rd, Cambridge CB2 1GA - England
Total Affiliations: 6
Document type: Journal article
Source: Journal of Medicinal Chemistry; v. 59, n. 7, p. 3272-3302, APR 14 2016.
Web of Science Citations: 23

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. (AU)

FAPESP's process: 11/21232-1 - Evaluation of the involvement of eIF5A in the secretory pathway in Saccharomyces cerevisiae
Grantee:Leonardo Biancolino Marino
Support Opportunities: Scholarships in Brazil - Doctorate (Direct)