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PDBsum entry 2cib
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Oxidoreductase
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PDB id
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2cib
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References listed in PDB file
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Key reference
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Title
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Small-Molecule scaffolds for cyp51 inhibitors identified by high-Throughput screening and defined by X-Ray crystallography.
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Authors
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L.M.Podust,
J.P.Von kries,
A.N.Eddine,
Y.Kim,
L.V.Yermalitskaya,
R.Kuehne,
H.Ouellet,
T.Warrier,
M.Alteköster,
J.S.Lee,
J.Rademann,
H.Oschkinat,
S.H.Kaufmann,
M.R.Waterman.
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Ref.
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Antimicrob Agents Chemother, 2007,
51,
3915-3923.
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PubMed id
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Abstract
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Sterol 14alpha-demethylase (CYP51), a major checkpoint in membrane sterol
biosynthesis, is a key target for fungal antibiotic therapy. We sought small
organic molecules for lead candidate CYP51 inhibitors. The changes in CYP51
spectral properties following ligand binding make CYP51 a convenient target for
high-throughput screening technologies. These changes are characteristic of
either substrate binding (type I) or inhibitor binding (type II) in the active
site. We screened a library of 20,000 organic molecules against Mycobacterium
tuberculosis CYP51 (CYP51(Mt)), examined the top type I and type II binding hits
for their inhibitory effects on M. tuberculosis in broth culture, and analyzed
them spectrally for their ability to discriminate between CYP51(Mt) and two
reference M. tuberculosis CYP proteins, CYP130 and CYP125. We determined the
binding mode for one of the top type II hits,
alpha-ethyl-N-4-pyridinyl-benzeneacetamide (EPBA), by solving the X-ray
structure of the CYP51(Mt)-EPBA complex to a resolution of 1.53 A. EPBA binds
coordinately to the heme iron in the CYP51(Mt) active site through a lone pair
of nitrogen electrons and also through hydrogen bonds with residues H259 and
Y76, which are invariable in the CYP51 family, and hydrophobic interactions in a
phylum- and/or substrate-specific cavity of CYP51. We also identified a second
compound with structural and binding properties similar to those of EPBA,
2-(benzo[d]-2,1,3-thiadiazole-4-sulfonyl)-2-amino-2-phenyl-N-(pyridinyl-4)-acetamide
(BSPPA). The congruence between the geometries of EPBA and BSPPA and the CYP51
binding site singles out EPBA and BSPPA as lead candidate CYP51 inhibitors with
optimization potential for efficient discrimination between host and pathogen
enzymes.
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