Substrate Fragmentation for the Design of M. tuberculosis CYP121 Inhibitors.

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Kavanagh, Madeline E 
Gray, Janine L 
Gilbert, Sophie H 
Coyne, Anthony G 
McLean, Kirsty J 

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.

drug discovery, enzymes, fragment-based methods, substrate analogues, tuberculosis, Anti-Bacterial Agents, Crystallography, X-Ray, Cytochrome P-450 Enzyme System, Dipeptides, Dose-Response Relationship, Drug, Drug Design, Enzyme Inhibitors, Microbial Sensitivity Tests, Models, Molecular, Molecular Conformation, Mycobacterium tuberculosis, Structure-Activity Relationship
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Biotechnology and Biological Sciences Research Council (BB/I019669/1)
Engineering and Physical Sciences Research Council (EP/K039520/1)
M.E.K. was supported by a Commonwealth (University of Cambridge) Scholarship awarded in conjunction with the Cambridge Commonwealth Trust and Cambridge Overseas Trust. A.G.C. and K.J.M. were supported by grants from the Biotechnology and Biological Sciences Research Council (BBSRC) (grant nos. BB/I019669/1 and BB/I019227/1). We acknowledge the support of the Wellcome Trust (Translation Award GR080083/Z/06).