1owj

File:1owj.jpg

spinqualitylabelsall models 1owj, resolution 3.10Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Substituted 2-Naphthamidine Inhibitors of Urokinase

OverviewOverview

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.

DiseaseDisease

Known disease associated with this structure: Alzheimer disease, late-onset, susceptibility to OMIM:[191840]

About this StructureAbout this Structure

1OWJ is a Single protein structure of sequence from Homo sapiens with as ligand. Active as U-plasminogen activator, with EC number 3.4.21.73 Full crystallographic information is available from OCA.

ReferenceReference

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., Wendt MD, Rockway TW, Geyer A, McClellan W, Weitzberg M, Zhao X, Mantei R, Nienaber VL, Stewart K, Klinghofer V, Giranda VL, J Med Chem. 2004 Jan 15;47(2):303-24. PMID:14711304

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