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Reverse type I inhibitor of Mycobacterium tuberculosis CYP125A1.

Ouellet H, Kells PM, Ortiz de Montellano PR, Podust LM
Bioorg Med Chem Lett 21 332-7 (2011)
Related entries: 2x5l, 2xc3

Cited: 18 times
EuropePMC logo PMID: 21109436

Abstract

Cytochrome P450 CYP125A1 of Mycobacterium tuberculosis, a potential therapeutic target for tuberculosis in humans, initiates degradation of the aliphatic chain of host cholesterol and is essential for establishing M. tuberculosis infection in a mouse model of disease. We explored the interactions of CYP125A1 with a reverse type I inhibitor by X-ray structure analysis and UV-vis spectroscopy. Compound LP10 (α-[(4-methylcyclohexyl)carbonyl amino]-N-4-pyridinyl-1H-indole-3-propanamide), previously identified as a potent type II inhibitor of Trypanosomacruzi CYP51, shifts CYP125A1 to a water-coordinated low-spin state upon binding with low micromolar affinity. When LP10 is present in the active site, the crystal structure and spectral characteristics both demonstrate changes in lipophilic and electronic properties favoring coordination of the iron axial water ligand. These results provide an insight into the structural requirements for developing selective CYP125A1 inhibitors.

Articles - 2xn8 mentioned but not cited (2)

  1. Reverse type I inhibitor of Mycobacterium tuberculosis CYP125A1. Ouellet H, Kells PM, Ortiz de Montellano PR, Podust LM. Bioorg Med Chem Lett 21 332-337 (2011)
  2. Significant reduction in errors associated with nonbonded contacts in protein crystal structures: automated all-atom refinement with PrimeX. Bell JA, Ho KL, Farid R. Acta Crystallogr D Biol Crystallogr 68 935-952 (2012)


Reviews citing this publication (5)

  1. Cholesterol catabolism as a therapeutic target in Mycobacterium tuberculosis. Ouellet H, Johnston JB, de Montellano PR. Trends Microbiol 19 530-539 (2011)
  2. Potential drug targets in the Mycobacterium tuberculosis cytochrome P450 system. Ortiz de Montellano PR. J Inorg Biochem 180 235-245 (2018)
  3. Cholesterol metabolism: a potential therapeutic target in Mycobacteria. Abuhammad A. Br J Pharmacol 174 2194-2208 (2017)
  4. Mycobacterium tuberculosis cytochrome P450 enzymes: a cohort of novel TB drug targets. Hudson SA, McLean KJ, Munro AW, Abell C. Biochem Soc Trans 40 573-579 (2012)
  5. Function, essentiality, and expression of cytochrome P450 enzymes and their cognate redox partners in Mycobacterium tuberculosis: are they drug targets? Ortega Ugalde S, Boot M, Commandeur JNM, Jennings P, Bitter W, Vos JC. Appl Microbiol Biotechnol 103 3597-3614 (2019)

Articles citing this publication (11)

  1. Diverse inhibitor chemotypes targeting Trypanosoma cruzi CYP51. Gunatilleke SS, Calvet CM, Johnston JB, Chen CK, Erenburg G, Gut J, Engel JC, Ang KK, Mulvaney J, Chen S, Arkin MR, McKerrow JH, Podust LM. PLoS Negl Trop Dis 6 e1736 (2012)
  2. Fragment-Based Approaches to the Development of Mycobacterium tuberculosis CYP121 Inhibitors. Kavanagh ME, Coyne AG, McLean KJ, James GG, Levy CW, Marino LB, de Carvalho LP, Chan DS, Hudson SA, Surade S, Leys D, Munro AW, Abell C. J Med Chem 59 3272-3302 (2016)
  3. Cholesterol ester oxidation by mycobacterial cytochrome P450. Frank DJ, Madrona Y, Ortiz de Montellano PR. J Biol Chem 289 30417-30425 (2014)
  4. Synthesis and antituberculosis activity of indole-pyridine derived hydrazides, hydrazide-hydrazones, and thiosemicarbazones. Velezheva V, Brennan P, Ivanov P, Kornienko A, Lyubimov S, Kazarian K, Nikonenko B, Majorov K, Apt A. Bioorg Med Chem Lett 26 978-985 (2016)
  5. Comparison of Antifungal Azole Interactions with Adult Cytochrome P450 3A4 versus Neonatal Cytochrome P450 3A7. Godamudunage MP, Grech AM, Scott EE. Drug Metab Dispos 46 1329-1337 (2018)
  6. Drug modulation of water-heme interactions in low-spin P450 complexes of CYP2C9d and CYP125A1. Conner KP, Cruce AA, Krzyaniak MD, Schimpf AM, Frank DJ, Frank DJ, Ortiz de Montellano P, Atkins WM, Bowman MK. Biochemistry 54 1198-1207 (2015)
  7. CW EPR parameters reveal cytochrome P450 ligand binding modes. Lockart MM, Rodriguez CA, Atkins WM, Bowman MK. J Inorg Biochem 183 157-164 (2018)
  8. Discovery and Biophysical Evaluation of First Low Nanomolar Hits Targeting CYP125 of M. tuberculosis. Brengel C, Thomann A, Schifrin A, Eberhard J, Hartmann RW. ChemMedChem 11 2385-2391 (2016)
  9. Multiple drug binding modes in Mycobacterium tuberculosis CYP51B1. Lockart MM, Butler JT, Mize CJ, Fair MN, Cruce AA, Conner KP, Atkins WM, Bowman MK. J Inorg Biochem 205 110994 (2020)
  10. Structure Based Discovery of Inhibitors of CYP125 and CYP142 from Mycobacterium tuberculosis. Katariya MM, Snee M, Tunnicliffe RB, Kavanagh ME, Boshoff HIM, Amadi CN, Levy CW, Munro AW, Abell C, Leys D, Coyne AG, McLean KJ. Chemistry 29 e202203868 (2023)
  11. Roles of cysteine in the structure and metabolic function of Mycobacterium tuberculosis CYP142A1. Lu Y, Sun L, Pang J, Li C, Wang X, Hu X, Li G, Li X, Zhang Y, Wang H, Yang X, You X. RSC Adv 12 24447-24455 (2022)


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