Deciphering the binding of dutasteride with human alpha-2-macroglobulin: Molecular docking and calorimetric approach

Dutasteride is a pharmacologically important drug employed to treat prostate cancer. Alpha-2-macroglobulin (alpha M-2) is the primary proteinase inhibitor and is abundant in vertebrate plasma. Previous studies have shown that alpha M-2 levels were down regulated in prostate cancer. Our results of functional assay shows 50% decrease in the antiproteolytic potential of alpha(2)Mupon its interaction with dutasteride. Fluorescence quenching revealed that dutasteride binds with alpha M-2 via static mechanism, resulting in the formation of dutasteride-alpha M-2 complex. Synchronous fluorescence studies suggest alteration in the microenvironment around tryptophan residues. Changes in the UV-visible spectra hints at formation of complex between the drug and protein. Secondary structural perturbations in alpha M-2 are confirmed by circular dichroism studies. Molecular docking discloses the involvement of hydrogen bonding during the interaction process and suggests the site of interaction of dutasteride on alpha M-2 monomer as Asn173, Lys171, Asp1178, Lys1236, His1182, Lys1177, Ser1180 and Lys1240.lsothermal titration calorimetry affirms the binding process to be spontaneous and exothermic. The results of this study may potentially be important should it be shown that dutasteride interacts with alpha M-2 under physiological conditions. (C) 2019 Elsevier B.V. All rights reserved.