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PDBsum entry 4be2
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Transferase/DNA
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PDB id
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4be2
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References listed in PDB file
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Key reference
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Title
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Activities, Crystal structures, And molecular dynamics of dihydro-1h-Isoindole derivatives, Inhibitors of HIV-1 integrase.
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Authors
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M.Métifiot,
K.Maddali,
B.C.Johnson,
S.Hare,
S.J.Smith,
X.Z.Zhao,
C.Marchand,
T.R.Burke,
S.H.Hughes,
P.Cherepanov,
Y.Pommier.
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Ref.
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Acs Chem Biol, 2013,
8,
209-217.
[DOI no: ]
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PubMed id
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Abstract
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On the basis of a series of lactam and phthalimide derivatives that inhibit
HIV-1 integrase, we developed a new molecule, XZ-259, with biochemical and
antiviral activities comparable to raltegravir. We determined the crystal
structures of XZ-259 and four other derivatives in complex with the prototype
foamy virus intasome. The compounds bind at the integrase-Mg(2+)-DNA interface
of the integrase active site. In biochemical and antiviral assays, XZ-259
inhibits raltegravir-resistant HIV-1 integrases harboring the Y143R mutation.
Molecular modeling is also presented suggesting that XZ-259 can bind in the
HIV-1 intasome with its dimethyl sulfonamide group adopting two opposite
orientations. Molecular dynamics analyses of the HIV-1 intasome highlight the
importance of the viral DNA in drug potency.
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