Multitarget fragment‐based design of novel inhibitors for AChE and SSAO/VAP‐1 enzymes

In Alzheimer's disease, increased human semicarbazide‐sensitive amine oxidase/vascular adhesion protein‐1 (SSAO/VAP‐1) expression has been found to colocalize with abnormal amyloid deposition. In addition, inhibition of acetylcholinesterase in Alzheimer's disease treatment should allow the lowered levels of acetylcholine in the synapses a chance to induce a signal in the downstream nerve. We designed inhibitors that interacted with both enzymes. The known inhibitors of acetylcholinesterase and SSAO/VAP‐1 were deconstructed into small fragments. Each fragment was docked to both enzymes, and the scoring function together with the ‘rule of three’ was used for fragment selection. The active fragments were combined with each other and resulted in 121 compounds. The docked pose of these compounds showed that seven compounds interacted in the binding site of both enzymes. Absorption, distribution, metabolism, elimination, and toxicity properties of these compounds were then calculated. The results showed that four of these inhibitors need to be synthesized for further experimental evaluation. Copyright © 2013 John Wiley & Sons, Ltd.