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PDBsum entry 3vf7
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Hydrolase/hydrolase inhibitor
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PDB id
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3vf7
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References listed in PDB file
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Key reference
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Title
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Potent antiviral HIV-1 protease inhibitor grl-02031 adapts to the structures of drug resistant mutants with its p1'-Pyrrolidinone ring.
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Authors
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Y.C.Chang,
X.Yu,
Y.Zhang,
Y.Tie,
Y.F.Wang,
S.Yashchuk,
A.K.Ghosh,
R.W.Harrison,
I.T.Weber.
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Ref.
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J Med Chem, 2012,
55,
3387-3397.
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PubMed id
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Abstract
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GRL-02031 (1) is an HIV-1 protease (PR) inhibitor containing a novel P1'
(R)-aminomethyl-2-pyrrolidinone group. Crystal structures at resolutions of
1.25-1.55 Å were analyzed for complexes of 1 with the PR containing major drug
resistant mutations, PR(I47V), PR(L76V), PR(V82A), and PR(N88D). Mutations of
I47V and V82A alter residues in the inhibitor-binding site, while L76V and N88D
are distal mutations having no direct contact with the inhibitor. Substitution
of a smaller amino acid in PR(I47V) and PR(L76V) and the altered charge of
PR(N88D) are associated with significant local structural changes compared to
the wild-type PR(WT), while substitution of alanine in PR(V82A) increases the
size of the S1' subsite. The P1' pyrrolidinone group of 1 accommodates to these
local changes by assuming two different conformations. Overall, the conformation
and interactions of 1 with PR mutants resemble those of PR(WT) with similar
inhibition constants in good agreement with the antiviral potency on multidrug
resistant HIV-1.
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