8S53

X-ray crystal structure of CYP142 from Mycobacterium tuberculosis in complex with a fragment bound in two poses

Summary for 8S53

• Entry DOI: 10.2210/pdb8s53/pdb
• Related: 2XKR 7P5T 7QQ7
• Descriptor: Steroid C26-monooxygenase, 4-benzylpyridine, PROTOPORPHYRIN IX CONTAINING FE, ... (4 entities in total)
• Functional Keywords: cyp142, p450, cholesterol, cytochrome, tuberculosis, fragment, heme, cyp, iron, drug, oxidoreductase
• Biological source: Mycobacterium tuberculosis H37Rv
• Total number of polymer chains: 1
• Total formula weight: 47571.68

Authors

Snee, M.,Kavanagh, M.,Levy, C.,Leys, D. (deposition date: 2024-02-22, release date: 2025-01-29, Last modification date: 2025-08-06)

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., 68:14416-14441, 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 (1.6 Å)