Reverse type I inhibitor of Mycobacterium tuberculosis CYP125A1

Bioorg Med Chem Lett. 2011 Jan 1;21(1):332-7. doi: 10.1016/j.bmcl.2010.11.007. Epub 2010 Nov 5.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Antitubercular Agents / chemistry*
  • Binding Sites
  • Catalytic Domain
  • Computer Simulation
  • Crystallography, X-Ray
  • Cytochrome P-450 Enzyme Inhibitors*
  • Cytochrome P-450 Enzyme System / genetics
  • Cytochrome P-450 Enzyme System / metabolism
  • Enzyme Inhibitors / chemistry*
  • Mycobacterium tuberculosis / enzymology*
  • Protein Binding
  • Spectrophotometry, Ultraviolet

Substances

  • Antitubercular Agents
  • Cytochrome P-450 Enzyme Inhibitors
  • Enzyme Inhibitors
  • Cytochrome P-450 Enzyme System

Associated data

  • PDB/2X5L
  • PDB/2XC3
  • PDB/2XN8