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Substrate Fragmentation for the Design of M. tuberculosis CYP121 Inhibitors
Author(s) -
Kavanagh Madeline E.,
Gray Janine L.,
Gilbert Sophie H.,
Coyne Anthony G.,
McLean Kirsty J.,
Davis Holly J.,
Munro Andrew W.,
Abell Chris
Publication year - 2016
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201600248
Subject(s) - pharmacophore , chemistry , enzyme , stereochemistry , ligand efficiency , ligand (biochemistry) , combinatorial chemistry , molecular model , dipeptide , biochemistry , amino acid , receptor
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 .