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PDBsum entry 3dm2
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References listed in PDB file
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Key reference
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Title
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Structural basis for the improved drug resistance profile of new generation benzophenone non-Nucleoside HIV-1 reverse transcriptase inhibitors.
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Authors
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J.Ren,
P.P.Chamberlain,
A.Stamp,
S.A.Short,
K.L.Weaver,
K.R.Romines,
R.Hazen,
A.Freeman,
R.G.Ferris,
C.W.Andrews,
L.Boone,
J.H.Chan,
D.K.Stammers.
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Ref.
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J Med Chem, 2008,
51,
5000-5008.
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PubMed id
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Abstract
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Owing to the emergence of resistant virus, next generation non-nucleoside HIV
reverse transcriptase inhibitors (NNRTIs) with improved drug resistance profiles
have been developed to treat HIV infection. Crystal structures of HIV-1 RT
complexed with benzophenones optimized for inhibition of HIV mutants that were
resistant to the prototype benzophenone GF128590 indicate factors contributing
to the resilience of later compounds in the series (GW4511, GW678248).
Meta-substituents on the benzophenone A-ring had the designed effect of inducing
better contacts with the conserved W229 while reducing aromatic stacking
interactions with the highly mutable Y181 side chain, which unexpectedly adopted
a "down" position. Up to four main-chain hydrogen bonds to the inhibitor also
appear significant in contributing to resilience. Structures of mutant RTs
(K103N, V106A/Y181C) with benzophenones showed only small rearrangements of the
NNRTIs relative to wild-type. Hence, adaptation to a mutated NNRTI pocket by
inhibitor rearrangement appears less significant for benzophenones than other
next-generation NNRTIs.
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