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PDBsum entry 2psu
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References listed in PDB file
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Key reference
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Title
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Design of mutation-Resistant HIV protease inhibitors with the substrate envelope hypothesis.
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Authors
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S.Chellappan,
G.S.Kiran kumar reddy,
A.Ali,
M.N.Nalam,
S.G.Anjum,
H.Cao,
V.Kairys,
M.X.Fernandes,
M.D.Altman,
B.Tidor,
T.M.Rana,
C.A.Schiffer,
M.K.Gilson.
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Ref.
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Chem Biol Drug Des, 2007,
69,
298-313.
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PubMed id
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Abstract
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There is a clinical need for HIV protease inhibitors that can evade resistance
mutations. One possible approach to designing such inhibitors relies upon the
crystallographic observation that the substrates of HIV protease occupy a rather
constant region within the binding site. In particular, it has been hypothesized
that inhibitors which lie within this region will tend to resist clinically
relevant mutations. The present study offers the first prospective evaluation of
this hypothesis, via computational design of inhibitors predicted to conform to
the substrate envelope, followed by synthesis and evaluation against wild-type
and mutant proteases, as well as structural studies of complexes of the designed
inhibitors with HIV protease. The results support the utility of the substrate
envelope hypothesis as a guide to the design of robust protease inhibitors.
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