5IBI

Crystal structure Mycobacterium tuberculosis CYP121 in complex with inhibitor fragment 26a

Summary for 5IBI

• Entry DOI: 10.2210/pdb5ibi/pdb
• Descriptor: Cytochrome P450 121 CYP121, SULFATE ION, 4,4'-(5-{[(4-hydroxyphenyl)methyl]amino}-1H-pyrazole-3,4-diyl)diphenol, ... (5 entities in total)
• Functional Keywords: mycobacterium tuberculosis cyp121 fragment based inhibitor screening, oxidoreductase
• Biological source: Mycobacterium tuberculosis
• Total number of polymer chains: 1
• Total formula weight: 44583.94

Authors

Levy, C. (deposition date: 2016-02-22, release date: 2016-04-06, Last modification date: 2024-05-01)

Primary citation

Kavanagh, M.E.,Coyne, A.G.,McLean, K.J.,James, G.G.,Levy, C.W.,Marino, L.B.,de Carvalho, L.P.,Chan, D.S.,Hudson, S.A.,Surade, S.,Leys, D.,Munro, A.W.,Abell, C.
Fragment-Based Approaches to the Development of Mycobacterium tuberculosis CYP121 Inhibitors.
J.Med.Chem., 59:3272-3302, 2016

PubMed 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.

PubMed: 27002486
DOI: 10.1021/acs.jmedchem.6b00007

Experimental method

X-RAY DIFFRACTION (2.2 Å)