Inhibition of acetylpolyamine and spermine oxidases by the polyamine analogue chlorhexidine.
Acetylpolyamine and spermine oxidases are involved in the catabolism of polyamines. The discovery of selective inhibitors of these enzymes represents an important tool for the development of novel anti-neoplastic drugs. Here, a comparative study on acetylpolyamine and spermine oxidases inhibition by the polyamine analogue chlorhexidine is reported. Chlorhexidine is an antiseptic diamide, commonly used as a bactericidal and bacteriostatic agent. Docking simulations indicate that chlorhexidine binding to these enzymes is compatible with the stereochemical properties of both acetylpolyamine oxidase and spermine oxidase active sites. In fact, chlorhexidine is predicted to establish several polar and hydrophobic interactions with the active site residues of both enzymes, with binding energy values ranging from -7.6 to -10.6 kcal/mol. In agreement with this hypothesis, inhibition studies indicate that chlorhexidine behaves as a strong competitive inhibitor of both enzymes, values of Ki being 0.10 μM and 0.55 μM for acetylpolyamine oxidase and spermine oxidase, respectively.
Department of Biology, University Roma Tre, Rome, Italy. cervelli@uniroma3.it
Manuela
M
Cervelli
Fabio
F
Polticelli
Laura
L
Fiorucci
Emanuela
E
Angelucci
Rodolfo
R
Federico
Paolo
P
Mariottini
D000818:Animals; D020134:Catalytic Domain; D002710:Chlorhexidine / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051379:Mice; D008958:Models, Molecular; D062105:Molecular Docking Simulation / Q000379:methods; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011487:Protein Conformation; D011700:Putrescine / Q000031:analogs & derivatives / Q000494:pharmacology; D000097667:Polyamine Oxidase
D002710:Chlorhexidine; D004791:Enzyme Inhibitors; D000587:Oxidoreductases Acting on CH-NH Group Donors; D011700:Putrescine; D000097667:Polyamine Oxidase; C044445:MDL 72527