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


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Authors

Kavanagh, Madeline E 
Coyne, Anthony G 
McLean, Kirsty J 
James, Guy G 
Levy, Colin W 

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.

Description

Keywords

Bacterial Proteins, Binding Sites, Crystallography, X-Ray, Cytochrome P-450 Enzyme System, Drug Design, Enzyme Inhibitors, Humans, Ligands, Mycobacterium tuberculosis, Protein Binding, Protein Structure, Tertiary, Tuberculosis

Journal Title

J Med Chem

Conference Name

Journal ISSN

0022-2623
1520-4804

Volume Title

59

Publisher

American Chemical Society (ACS)
Sponsorship
Biotechnology and Biological Sciences Research Council (BB/I019669/1)
Engineering and Physical Sciences Research Council (EP/K039520/1)
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).