Reverse type I inhibitor of Mycobacterium tuberculosis CYP125A1

doi:10.1016/j.bmcl.2010.11.007

Bioorganic & Medicinal Chemistry Letters

Volume 21, Issue 1, 1 January 2011, Pages 332-337

https://doi.org/10.1016/j.bmcl.2010.11.007 Get rights and content

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 Trypanosoma cruzi 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.

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Acknowledgments

We thank Mr. Potter Wickware for critical reading of the manuscript, the staff members of beamline 8.3.1, James Holton, George Meigs and Jane Tanamachi, at the Advanced Light Source at Lawrence Berkeley National Laboratory, for assistance with data collection. This work was supported by National Institutes of Health RO1 Grants GM078553 (to L.M.P.), GM25515 and AI74824 (to P.O.M.). The Advanced Light Source is supported by the Director, Office of Science, Office of Basic Energy Sciences, of the

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CYP crystal structures containing drugs or substrates occasionally have binding modes that neither replace nor displace the axial water. The complexes of CYP125A1 with α‑[(4‑methylcyclohexyl)carbonyl amino]‑N‑4‑pyridinyl‑1H‑indole‑3‑propanamide (LP10), Fig. 1 [16]; CYP121A1 with fluconazole [17]; CYP121 with cyclodityrosine [18]; and possibly CYP101A1 with 2-phenylimidazole [8] all show drug or substrate in the binding pocket with the axial water intact and forming a hydrogen-bonded bridge to the drug. The crystal structure of the complex of CYP121A1 with fluconazole is notable because it contains different mixtures of water-bridged and directly-coordinated fluconazoles in each of the six CYP121A molecules that make up the asymmetric unit, suggesting that the binding energies are so similar that the two binding modes coexist in the crystal [17].
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Reverse type I inhibitor of Mycobacterium tuberculosis CYP125A1

Abstract

Graphical abstract

Section snippets

Acknowledgments

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Arch. Biochem. Biophys.

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Methods Enzymol.

Structure

J. Biol. Chem.

Drug Discovery Today

Proc. Natl. Acad. Sci. U.S.A.

Proc. Natl. Acad. Sci. U.S.A.

Proc. Natl. Acad. Sci. U.S.A.

Mol. Microbiol.

J. Infect. Dis.

Proc. Natl. Acad. Sci. U.S.A.

J. Bacteriol.

PLoS Pathog.

Mol. Microbiol.