Mechanism of Activation of an Immunosuppressive Drug:  Azathioprine. Quantum Chemical Study on the Reaction of Azathioprine with Cysteine

Abstract

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.

The interactome: Predicting the protein-protein interactions in cells

“…Proper selection of the protein domain is necessary [102][103][104][105][106][107][108]. In addition to pure chemical data [109][110][111][112][113][114][115][116] in the context of the Drug Discovery [117][118][119][120][121][122][123][124][125][126][127], there is also a need for some knowledge on protein-protein interactions, the high quality structural prediction of proteins [2,[128][129][130][131][132][133][134][135][136] and their inhibitors, and a detailed understanding of how those inhibitors affect the molecular recognition between proteins. The development of theoretical methods for function annotation clearly shows that a detailed analysis of local characteristics of the protein chain can significantly improve accuracy.…”

Azathioprine in dermatology: The past, the present, and the future

“…20,[28][29][30][31] Azathioprine is rapidly, nonenzymatically cleaved in vivo by ubiquitous sulfhydryl compounds (cysteine, glutathione, hydrogen sulfide, other thiols, or possibly proteins). 20,27,32 Quantum mechanical methods have been used recently to elucidate this first critical step by establishing that it results from the COO e , SH, and NH 3 groups on these biogenic thiols. 32 The product of this cleavage results in separation of the 2 principal moieties, mercaptopurine and the imidazole derivative (methylnitroimidazole).…”

CD28-dependent Rac1 activation is the molecular target of azathioprine in primary human CD4+ T lymphocytes

“…The azathioprine molecule is composed of two moieties: mercaptopurine and an imidazole derivative (14,18). After oral administration and absorption, the prodrug azathioprine undergoes approximately 90% conversion to 6-MP by nonenzymatic attack by sulphydrylcontaining compounds such as glutathione or cysteine that are present in every mammalian cell (14,19).…”