7ZIC

Crystal structure of CYP125 from Mycobacterium tuberculosis in complex with an inhibitor

Summary for 7ZIC

• Entry DOI: 10.2210/pdb7zic/pdb
• Related: 7P5T 7ZGL
• Descriptor: Steroid C26-monooxygenase, GLYCEROL, ~{N}-[(4-methoxyphenyl)methyl]-4-(pyridin-4-ylmethyl)aniline, ... (7 entities in total)
• Functional Keywords: cyp, cyp125, p450, cholesterol, oxidase, inhibitor, complex, cytochrome, tuberculosis, mtb, mycobacterium, monooxygenase, oxidoreductase
• Biological source: Mycobacterium tuberculosis H37Rv
• Total number of polymer chains: 3
• Total formula weight: 144452.78

Authors

Snee, M.,Levy, C.,Kavanagh, M. (deposition date: 2022-04-07, release date: 2023-04-19, Last modification date: 2025-07-30)

Primary citation

Kavanagh, M.E.,McLean, K.J.,Gilbert, S.H.,Amadi, C.N.,Snee, M.,Tunnicliffe, R.B.,Arora, K.,Boshoff, H.I.M.,Fanourakis, A.,Rebollo-Lopez, M.J.,Ortega, F.,Levy, C.W.,Munro, A.W.,Leys, D.,Abell, C.,Coyne, A.G.
Fragment-Based Development of Small Molecule Inhibitors Targeting Mycobacterium tuberculosis Cholesterol Metabolism.
J.Med.Chem., 2025

PubMed Abstract: Tuberculosis is the deadliest infectious disease in history and new drugs are urgently required to combat multidrug-resistant (MDR) strains of (). Here, we exploit the relience of on host-derived cholesterol to develop a novel class of antitubercular compounds that target CYP125 and CYP142; the enzymes that catalyze the first step of cholesterol metabolism. A combination of fragment screening and structure-based drug design was used to identify a hit compound and guide synthetic optimization of a dual CYP125/142 ligand ( 40-160 nM), which potently inhibits enzyme activity in vitro ( < 100 nM), and the growth of in extracellular (MIC 0.4-1.5 μM) and intracellular assays (IC 1.7 μM). The structural data and lead compounds reported here will help study cholesterol metabolism and guide the development of novel antibiotics to combat MDR

PubMed: 40653654
DOI: 10.1021/acs.jmedchem.5c00478

Experimental method

X-RAY DIFFRACTION (1.9 Å)