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PDBsum entry 4cod
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PDB id:
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Transferase
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Title:
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Encoded library technology as a source of hits for the discovery and lead optimization of a potent and selective class of bactericidal direct inhibitors of mycobacterium tuberculosis inha
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Structure:
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Enoyl-[acyl-carrier-protein] reductase [nadh]. Chain: b, d, f, h. Synonym: nadh-dependent enoyl-acp reductase, enoyl-acyl carrier prot ein reductase. Engineered: yes
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Source:
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Mycobacterium tuberculosis. Organism_taxid: 1773. Expressed in: escherichia coli. Expression_system_taxid: 469008.
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Resolution:
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2.40Å
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R-factor:
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0.172
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R-free:
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0.206
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Authors:
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L.Encinas,H.Okeefe,M.Neu,M.A.Convery,W.Mcdowell,A.Mendoza-Losana, L.B.Pages,J.Castro-Pichel,G.Evindar
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Key ref:
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L.Encinas
et al.
(2014).
Encoded library technology as a source of hits for the discovery and lead optimization of a potent and selective class of bactericidal direct inhibitors of Mycobacterium tuberculosis InhA.
J Med Chem,
57,
1276-1288.
PubMed id:
DOI:
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Date:
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28-Jan-14
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Release date:
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12-Feb-14
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PROCHECK
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Headers
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References
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P9WGR1
(INHA_MYCTU) -
Enoyl-[acyl-carrier-protein] reductase [NADH] from Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)
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Seq:
Struc:
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269 a.a.
268 a.a.
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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Enzyme class:
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E.C.1.3.1.9
- enoyl-[acyl-carrier-protein] reductase (NADH).
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Reaction:
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a 2,3-saturated acyl-[ACP] + NAD+ = a (2E)-enoyl-[ACP] + NADH + H+
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2,3-saturated acyl-[ACP]
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+
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NAD(+)
Bound ligand (Het Group name = )
corresponds exactly
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=
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(2E)-enoyl-[ACP]
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+
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NADH
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+
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H(+)
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Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
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DOI no:
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J Med Chem
57:1276-1288
(2014)
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PubMed id:
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Encoded library technology as a source of hits for the discovery and lead optimization of a potent and selective class of bactericidal direct inhibitors of Mycobacterium tuberculosis InhA.
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L.Encinas,
H.O'Keefe,
M.Neu,
M.J.Remuiñán,
A.M.Patel,
A.Guardia,
C.P.Davie,
N.Pérez-Macías,
H.Yang,
M.A.Convery,
J.A.Messer,
E.Pérez-Herrán,
P.A.Centrella,
D.Alvarez-Gómez,
M.A.Clark,
S.Huss,
G.K.O'Donovan,
F.Ortega-Muro,
W.McDowell,
P.Castañeda,
C.C.Arico-Muendel,
S.Pajk,
J.Rullás,
I.Angulo-Barturen,
E.Alvarez-Ruíz,
A.Mendoza-Losana,
L.Ballell Pages,
J.Castro-Pichel,
G.Evindar.
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ABSTRACT
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Tuberculosis (TB) is one of the world's oldest and deadliest diseases, killing a
person every 20 s. InhA, the enoyl-ACP reductase from Mycobacterium
tuberculosis, is the target of the frontline antitubercular drug isoniazid
(INH). Compounds that directly target InhA and do not require activation by
mycobacterial catalase peroxidase KatG are promising candidates for treating
infections caused by INH resistant strains. The application of the encoded
library technology (ELT) to the discovery of direct InhA inhibitors yielded
compound 7 endowed with good enzymatic potency but with low antitubercular
potency. This work reports the hit identification, the selected strategy for
potency optimization, the structure-activity relationships of a hundred
analogues synthesized, and the results of the in vivo efficacy studies performed
with the lead compound 65.
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