Reverse type I inhibitor of Mycobacteriumtuberculosis CYP125A1 |
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Authors: | Hugues OuelletPetrea M Kells Paul R Ortiz de MontellanoLarissa M Podust |
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Institution: | Department of Pharmaceutical Chemistry and Sandler Center for Drug Discovery, University of California, San Francisco, CA 94158, USA |
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Abstract: | Cytochrome P450 CYP125A1 of Mycobacteriumtuberculosis, 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. |
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Keywords: | P450 CYP125 Mycobacterium tuberculosis Cholesterol degradation CYP125-inhibitor complex X-ray structure |
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