Substrate Fragmentation for the Design of M. tuberculosis CYP121 Inhibitors

Madeline E. Kavanagh, Janine L. Gray, Sophie H. Gilbert, Anthony G. Coyne, Kirsty J. McLean, Holly J. Davis, Andrew W. Munro, Chris Abell

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

The cyclo-dipeptide substrates of the essential M. tuberculosis (Mtb) enzyme CYP121 were deconstructed into their component fragments and screened against the enzyme. A number of hits were identified, one of which exhibited an unexpected inhibitor-like binding mode. The inhibitory pharmacophore was elucidated, and fragment binding affinity was rapidly improved by synthetic elaboration guided by the structures of CYP121 substrates. The resulting inhibitors have low micromolar affinity, good predicted physicochemical properties and selectivity for CYP121 over other Mtb P450s. Spectroscopic characterisation of the inhibitors′ binding mode provides insight into the effect of weak nitrogen-donor ligands on the P450 heme, an improved understanding of factors governing CYP121–ligand recognition and speculation into the biological role of the enzyme for Mtb.

Original languageEnglish
Pages (from-to)1924-1935
Number of pages12
JournalChemMedChem
Volume11
Issue number17
Early online date19 Jul 2016
DOIs
Publication statusPublished - 6 Sep 2016
Externally publishedYes

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    Kavanagh, M. E., Gray, J. L., Gilbert, S. H., Coyne, A. G., McLean, K. J., Davis, H. J., Munro, A. W., & Abell, C. (2016). Substrate Fragmentation for the Design of M. tuberculosis CYP121 Inhibitors. ChemMedChem, 11(17), 1924-1935. https://doi.org/10.1002/cmdc.201600248