A combined photophysical and computational study on the binding of mycophenolate mofetil and its major metabolite to transport proteins

作者：Vendrell Criado Victoria; Gonzalez Bello Concepcion; Miranda Miguel A; Consuelo Jimenez M

来源：Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy , 2018, 199: 308-314.

DOI：10.1016/j.saa.2018.03.064

• Drug-protein binding
• Docking
• Fluorescence
• Human serum albumin
• Human alpha(1)-acid glycoprotein

Binding of the immunosuppressive agent mycophenolate mofetil (MMP) and its pharmacologically active metabolite mycophenolic acid (MPA) to human serum albumin (HSA) and alpha(1)-acid glycoprotein (HAAG) has been investigated by means of an integrated approach involving selective excitation of the drug fluorophore, following their UV-A triggered fluorescence and docking studies. The formation of the protein/ligand complexes was evidenced by a dramatic enhancement of the fluorescence intensity and a hypsochromic shift of the emission band. In HSA, competitive studies using oleic acid as site I probe revealed site I as the main binding site of the ligands. Binding constants revealed that the affinity of the active metabolite by HSA is four-fold higher than its proactive form. Moreover, the affinity of MMP by HSA is three-fold higher than by HAAG. Docking studies revealed significant molecular binding differences in the binding of MMP and MPA to sub-domain IIA of HSA (site 1). For MPA, the aromatic moiety would be in close contact to Trp214 with the flexible chain pointing to the other end of the sub-domain; on the contrary, for MMP, the carboxylate group of the chain would be fixed nearby Trp214 through electrostatic interactions with residues Arg218 and Arg222.

• 出版日期2018-6-15