Mechanism of activation of an immunosuppressive drug: azathioprine. Quantum chemical study on the reaction of azathioprine with cysteine.
Azathioprine is an important drug used in the therapy of autoimmune disorders and in preventing graft rejection. Its molecule is composed of two main moieties: mercaptopurine and imidazole derivative. It is an immunosuppressive agent whose biological activity results from its in vivo mercaptolysis mediated by a nucleophilic attack on the C(5i) atom of imidazole ring of the azathioprine molecule. Solvation model SM5.4 with the PM3 Hamiltonian have been applied to model the reaction of azathioprine with cysteine. The employed quantum mechanical method shed new light on the mechanism of the reaction of azathioprine with cysteine in aqueous solution. The obtained results indicated that the first step in the reaction most likely involves the nucleophilic attack of the COO(-) of cysteine on the C(5i) atom of the imidazole ring of azathioprine, followed by a subsequent intramolecular attack of the SH group of the cysteine residue. It was shown that biogenic thiols such as glutathione or cysteine facilitate the first and crucial step of azathioprine metabolism, due to the presence of COO(-), SH, and NH(3)(+) groups in their molecules.
Hoffmann
M
M
Quantum Chemistry Group, Faculty of Chemistry, A. Mickiewicz University, ul. Grunwaldzka 6, 60-780 Poznan, Poland.
Rychlewski
J
J
Chrzanowska
M
M
Hermann
T
T
D001379:Azathioprine / Q000737:chemistry* / Q000494:pharmacology*; D003545:Cysteine / Q000737:chemistry* / Q000378:metabolism*; D007093:Imidazoles / Q000737:chemistry; D007166:Immunosuppressive Agents / Q000737:chemistry* / Q000494:pharmacology*; D015122:Mercaptopurine / Q000737:chemistry; D008962:Models, Theoretical; D008968:Molecular Conformation; D015394:Molecular Structure
D007093:Imidazoles; D007166:Immunosuppressive Agents; D015122:Mercaptopurine; D003545:Cysteine; D001379:Azathioprine