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PDBsum entry 1owi
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Identification of novel binding interactions in the development of potent, Selective 2-Naphthamidine inhibitors of urokinase. Synthesis, Structural analysis, And sar of n-Phenyl amide 6-Substitution.
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Authors
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M.D.Wendt,
T.W.Rockway,
A.Geyer,
W.Mcclellan,
M.Weitzberg,
X.Zhao,
R.Mantei,
V.L.Nienaber,
K.Stewart,
V.Klinghofer,
V.L.Giranda.
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Ref.
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J Med Chem, 2004,
47,
303-324.
[DOI no: ]
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PubMed id
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Abstract
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The preparation and assessment of biological activity of 6-substituted
2-naphthamidine inhibitors of the serine protease urokinase plasminogen
activator (uPA, or urokinase) is described. 2-Naphthamidine was chosen as a
starting point based on synthetic considerations and on modeling of substituent
vectors. Phenyl amides at the 6-position were found to improve binding;
replacement of the amide with other two-atom linkers proved ineffective. The
phenyl group itself is situated near the S1' subsite; substitutions off of the
phenyl group accessed S1' and other distant binding regions. Three new points of
interaction were defined and explored through ring substitution. A
solvent-exposed salt bridge with the Asp60A carboxylate was formed using a
4-alkylamino group, improving affinity to K(i) = 40 nM. Inhibitors also accessed
two hydrophobic regions. One interaction is characterized by a tight hydrophobic
fit made with a small dimple largely defined by His57 and His99; a weaker, less
specific interaction involves alkyl groups reaching into the broad prime-side
protein binding region near Val41 and the Cys42-Cys58 disulfide, displacing
water molecules and leading to small gains in activity. Many inhibitors accessed
two of these three regions. Affinities range as low as K(i) = 6 nM, and many
compounds had K(i) < 100 nM, while moderate to excellent selectivity was
gained versus four of five members of a panel of relevant serine proteases.
Also, some selectivity against trypsin was generated via the interaction with
Asp60A. X-ray structures of many of these compounds were used to inform our
inhibitor design and to increase our understanding of key interactions. In
combination with our exploration of 8-substitution patterns, we have identified
a number of novel binding interactions for uPA inhibitors.
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