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5-Fluorouracil (5-FU) is a well-recognized anticancer drug used in the treatment of tumors of head, neck and breast. Drug pharmacokinetics is affected upon binding with protein, thus, making drug–protein interactions imperative to study. Present work investigates the interaction between 5-FU and human major antiproteinase-alpha-2-macroglobulin (α 2 M) by multi-spectroscopic, calorimetric and molecular docking techniques. UV/Visible absorption, intrinsic fluorescence and circular dichroism (CD) spectroscopic methods have been employed to unveil the mode and mechanism of 5-FU-α 2 M interaction. Synchronous fluorescence showed alteration in the microenvironment of tryptophan and tyrosine residues of protein. Far UV-CD spectra suggest slight alterations in the secondary structure of α 2 M by 5-FU. Thermodynamic parameters determined by fluorescence quenching experiments and isothermal titration calorimetry (ITC) suggested the involvement of hydrogen bonds and hydrophobic interactions. Moreover, ITC corroborate the spontaneous and exothermic nature of the interaction process. Molecular docking illustrates that 5-FU binds with moderate affinity and Asp953, Tyr1264, Lys1236, Thr1232, Tyr1323 and Leu951 were the main residues involved. Molecular dynamics simulation studies suggested that 5-FU was stabilizing the α 2 M structure and forming a stable complex. It was concluded that 5-FU lower the antiproteolytic activity of α 2 M significantly and causes disruption in the native structure and conformation of α 2 M. Communicated by Ramaswamy H. Sarma

Characterization of the binding between anti-tumor drug 5-fluorouracil and human alpha-2-macroglobulin: spectroscopic and molecular docking analyses