1OWD

Substituted 2-Naphthamidine inhibitors of urokinase

Summary for 1OWD

• Entry DOI: 10.2210/pdb1owd/pdb
• Related: 1FV9 1OWE 1OWH 1OWI 1OWJ 1OWK
• Descriptor: Urokinase-type plasminogen activator, 6-[AMINO(IMINO)METHYL]-N-[(4R)-4-ETHYL-1,2,3,4-TETRAHYDROISOQUINOLIN-6-YL]-2-NAPHTHAMIDE (3 entities in total)
• Functional Keywords: plasminogen activation, hydrolase, serine protease, glycoprotein, kringle, egf-like domain
• Biological source: Homo sapiens (human)
• Cellular location: Secreted: P00749
• Total number of polymer chains: 1
• Total formula weight: 27994.96

Authors

Wendt, M.D.,Rockway, T.W.,Geyer, A.,McClellan, W.,Weitzberg, M.,Zhao, X.,Mantei, R.,Nienaber, V.L.,Stewart, K.,Klinghofer, V.,Giranda, V.L. (deposition date: 2003-03-28, release date: 2003-09-30, Last modification date: 2017-10-11)

Primary citation

Wendt, M.D.,Rockway, T.W.,Geyer, A.,McClellan, W.,Weitzberg, M.,Zhao, X.,Mantei, R.,Nienaber, V.L.,Stewart, K.,Klinghofer, V.,Giranda, V.L.
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.
J.Med.Chem., 47:303-324, 2004

PubMed Abstract: 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.

PubMed: 14711304
DOI: 10.1021/jm0300072

Experimental method

X-RAY DIFFRACTION (2.32 Å)