1owj: Difference between revisions
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==Overview== | ==Overview== | ||
The preparation and assessment of biological activity of 6-substituted | 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. | ||
==Disease== | ==Disease== | ||
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[[Category: U-plasminogen activator]] | [[Category: U-plasminogen activator]] | ||
[[Category: Geyer, A.]] | [[Category: Geyer, A.]] | ||
[[Category: Giranda, V | [[Category: Giranda, V L.]] | ||
[[Category: Klinghofer, V.]] | [[Category: Klinghofer, V.]] | ||
[[Category: Mantei, R.]] | [[Category: Mantei, R.]] | ||
[[Category: McClellan, W.]] | [[Category: McClellan, W.]] | ||
[[Category: Nienaber, V | [[Category: Nienaber, V L.]] | ||
[[Category: Rockway, T | [[Category: Rockway, T W.]] | ||
[[Category: Stewart, K.]] | [[Category: Stewart, K.]] | ||
[[Category: Weitzberg, M.]] | [[Category: Weitzberg, M.]] | ||
[[Category: Wendt, M | [[Category: Wendt, M D.]] | ||
[[Category: Zhao, X.]] | [[Category: Zhao, X.]] | ||
[[Category: 155]] | [[Category: 155]] | ||
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[[Category: serine protease]] | [[Category: serine protease]] | ||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:22:26 2008'' | ||
Revision as of 15:22, 21 February 2008
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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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