Exploring the Binding Mode of Semicarbazide-Sensitive Amine Oxidase/VAP-1:  Identification of Novel Substrates with Insulin-like Activity

• Published in: Journal of medicinal chemistry Vol. 47; no. 20; pp. 4865 - 4874
• Main Authors: Marti, Luc, Abella, Anna, de la Cruz, Xavier, García-Vicente, Silvia, Unzeta, Mercedes, Carpéné, Christian, Palacín, Manuel, Testar, Xavier, Orozco, Modesto, Zorzano, Antonio
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 23.09.2004
• Subjects: Adipocytes - drug effects; Adipocytes - metabolism; Amine Oxidase (Copper-Containing) - chemistry; Amine Oxidase (Copper-Containing) - drug effects; Amine Oxidase (Copper-Containing) - metabolism; Amines - metabolism; Amino Acid Sequence; Animals; Benzylamines - metabolism; Benzylamines - pharmacology; Binding Sites; Biological and medical sciences; Biological Transport; Catalytic Domain; Cell Adhesion Molecules - chemistry; Cell Adhesion Molecules - drug effects; Cell Adhesion Molecules - metabolism; Cells, Cultured; Drug Evaluation, Preclinical - methods; General and cellular metabolism. Vitamins; Glucose - metabolism; Humans; Insulin - metabolism; Insulin - pharmacology; Male; Medical sciences; Methylamines - chemistry; Methylamines - metabolism; Methylamines - pharmacology; Mice; Models, Molecular; Molecular Sequence Data; Naphthalenes - chemistry; Naphthalenes - metabolism; Naphthalenes - pharmacology; Pharmacology. Drug treatments; Protein Conformation; Rats; Rats, Wistar; Sequence Homology, Amino Acid; Substrate Specificity; Vanadates - metabolism; Vanadates - pharmacology; Adipocyte; Rat; Biological transport; Homology; Glucose; Modeling; Pyrrolidine derivatives; Amine; Benzylic compound; Chemical compound library; Molecular model; Binding mode; Enzyme; Mimetic; Rodentia; Quinoline derivatives; Insulin; Biological activity; Amine oxidase (copper-containing); Substrate; Vertebrata; Mammalia; Mouse; Animal; Oxidoreductases
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0499211

We previously reported that substrates of semicarbazide-sensitive amine oxidase in combination with low concentrations of vanadate exert potent insulin-like effects. Here we performed homology modeling of the catalytic domain of mouse SSAO/VAP-1 and searched through chemical databases to identify novel SSAO substrates. The modeling of the catalytic domain revealed that aromatic residues Tyr384, Phe389, and Tyr394 define a pocket of stable size that may participate in the binding of apolar substrates. We identified a number of amines as substrates of human, rat, and mouse SSAO. The compounds PD0119035, 2,3-dimethoxy-benzylamine, and C-naphthalen-1-yl-methylamine showed high affinity as substrates of rat SSAO. C-Naphthalen-1-yl-methylamine was the only substrate that showed high affinity for human SSAO. C-Naphthalen-1-yl-methylamine and 4-aminomethyl-benzenesulfonamide showed the highest capacity to stimulate glucose transport in isolated rat adipocytes. The impact of these findings on the development of new treatments for diabetes is discussed.