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 (α ₂ M) is the primary proteinase inhibitor and is abundant in vertebrate plasma. Previous studies have shown that α ₂ M levels were down regulated in prostate cancer. Our results of functional assay shows 50% decrease in the antiproteolytic potential ofα ₂ Mupon its interaction with dutasteride. Fluorescence quenching revealed that dutasteride binds with α ₂ M via static mechanism, resulting in the formation of dutasteride-α ₂ M 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 α ₂ M 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 α ₂ M monomer as Asn173, Lys171, Asp1178, Lys1236, His1182, Lys1177, Ser1180 and Lys1240.Isothermal 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 α ₂ M under physiological conditions.
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