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PDBsum entry 4jvq
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Hydrolase/hydrolase inhibitor
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PDB id
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4jvq
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References listed in PDB file
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Key reference
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Title
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Enantiomeric atropisomers inhibit hcv polymerase and/or HIV matrix: characterizing hindered bond rotations and target selectivity.
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Authors
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S.R.Laplante,
P.Forgione,
C.Boucher,
R.Coulombe,
J.Gillard,
O.Hucke,
A.Jakalian,
M.A.Joly,
G.Kukolj,
C.Lemke,
R.Mccollum,
S.Titolo,
P.L.Beaulieu,
T.Stammers.
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Ref.
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J Med Chem, 2014,
57,
1944-1951.
[DOI no: ]
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PubMed id
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Abstract
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An anthranilic acid series of allosteric thumb pocket 2 HCV NS5B polymerase
inhibitors exhibited hindered rotation along a covalent bond axis, and the
existence of atropisomer chirality was confirmed by NMR, HPLC analysis on chiral
supports, and computational studies. A thorough understanding of the concerted
rotational properties and the influence exerted by substituents involved in this
steric phenomenon was attained through biophysical studies on a series of
truncated analogues. The racemization half-life of a compound within this series
was determined to be 69 min, which was consistent with a class 2 atropisomer
(intermediate conformational exchange). It was further found by X-ray
crystallography that one enantiomer of a compound bound to the intended HCV NS5B
polymerase target whereas the mirror image atropisomer was able to bind to an
unrelated HIV matrix target. Analogues were then identified that selectively
inhibited the former. These studies highlight that atropisomer chirality can
lead to distinct entities with specific properties, and the phenomenon of
atropisomerism in drug discovery should be evaluated and appropriately managed.
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