Human Copper-Containing Amine Oxidases in Drug Design and Development.
Serhii VakalSirpa JalkanenKäthe M DahlströmTiina A SalminenPublished in: Molecules (Basel, Switzerland) (2020)
Two members of the copper-containing amine oxidase family are physiologically important proteins: (1) Diamine oxidase (hDAO; AOC1) with a preference for diamines is involved in degradation of histamine and (2) Vascular adhesion protein-1 (hVAP-1; AOC3) with a preference for monoamines is a multifunctional cell-surface receptor and an enzyme. hVAP-1-targeted inhibitors are designed to treat inflammatory diseases and cancer, whereas the off-target binding of the designed inhibitors to hDAO might result in adverse drug reactions. The X-ray structures for both human enzymes are solved and provide the basis for computer-aided inhibitor design, which has been reported by several research groups. Although the putative off-target effect of hDAO is less studied, computational methods could be easily utilized to avoid the binding of VAP-1-targeted inhibitors to hDAO. The choice of the model organism for preclinical testing of hVAP-1 inhibitors is not either trivial due to species-specific binding properties of designed inhibitors and different repertoire of copper-containing amine oxidase family members in mammalian species. Thus, the facts that should be considered in hVAP-1-targeted inhibitor design are discussed in light of the applied structural bioinformatics and structural biology approaches.
Keyphrases
- adverse drug
- cancer therapy
- endothelial cells
- cell surface
- binding protein
- high resolution
- drug delivery
- stem cells
- squamous cell carcinoma
- oxidative stress
- dna binding
- magnetic resonance imaging
- escherichia coli
- staphylococcus aureus
- small molecule
- pseudomonas aeruginosa
- young adults
- cystic fibrosis
- drug induced
- biofilm formation