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

摘要

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.