Kavanagh, Madeline E.Coyne, Anthony G.McLean, Kirsty J.James, Guy G.Levy, Colin W.Marino, Leonardo B. [UNESP]De Carvalho, Luiz Pedro S.Chan, Daniel S. H.Hudson, Sean A.Surade, SachinLeys, DavidMunro, Andrew W.Abell, Chris2018-12-112018-12-112016-04-28Journal of Medicinal Chemistry, v. 59, n. 7, p. 3272-3302, 2016.1520-48040022-2623http://hdl.handle.net/11449/168631The 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.3272-3302engArtigo10.1021/acs.jmedchem.6b00007Acesso restrito2-s2.0-84966283595